Topical diphenylcyclopropenone plus topical 0.5% anthralin versus topical diphenylcyclopropenone alone for the treatment of chronic extensive alopecia areata: A split-scalp, double-blind, controlled study.

Background: The combination of diphenylcyclopropenone (DCP) and anthralin may demonstrate synergistic effects in the treatment of chronic extensive alopecia areata (AA). Objective: The objective of the study was to compare the efficacy of the combination therapy of topical DCP and topical 0.5% anthralin versus topical DCP alone for the treatment of chronic extensive AA. Materials and
Methods: Ten patients were included in the study. Of these, 1, 2, and 7 patients were diagnosed with alopecia totalis, severe AA (>50% hair loss), and alopecia universalis, respectively. For each patient, one side of the scalp was treated with a DCP solution and 0.5% anthralin for 6 months, while the other side was treated with DCP and a cream base for the same duration. The clinical responses were assessed at baseline and then monthly until the end of the 6-month study period using the Severity of Alopecia Tool score. The side effects were evaluated at each follow-up visit.
Results: The difference in the efficacies of the combination treatment and DCP alone was not statistically significant (P = 0.59). Regarding the side effects, DCP plus 0.5% anthralin caused significantly more excessive dermatitis than DCP alone (7 patients vs. 2 patients; P = 0.02). Eight patients reported temporary hyperpigmentation at the combination-treatment site, whereas no hyperpigmentation was reported at the DCP-alone site of any patient (P < 0.001). Conclusions: The combination of DCP and 0.5% anthralin was not superior to DCP alone for the treatment of chronic extensive AA. An increase in side effects - excessive dermatitis and hyperpigmentation - was observed in the combination-treatment group. Copyright:

INTRODUCTION

Alopecia areata (AA) is a recurrent nonscarring alopecia that commonly presents with round discrete patches of hair loss on hair-bearing areas. The pathophysiology of AA is unknown. Current evidence suggests that AA is an autoimmune disease that causes a lymphocyte-cell-mediated, inflammatory form of hair loss.[1] Infiltration of cytotoxic T-lymphocytes around and within hair follicles leads to the destruction of the follicles during the anagen phase, thereby disrupting the hair cycle.[1] Environmental factors, such as stress, may trigger the development of AA.[2] The severe and extensive forms of AA are alopecia totalis (AT; defined as a total loss of scalp hair) and alopecia universalis (AU; defined as a total loss of both scalp and body hair).

The treatment of AA includes topical immunotherapy, topical steroids, oral immunosuppressive agents, and photodynamic therapy.[3] Some AA patients have spontaneous hair regrowth without treatment or require only topical or intralesional corticosteroid injections. However, the treatment of chronic extensive AA is difficult and lengthy. Less than 10% of the AU patients have complete spontaneous hair regrowth.[45] Diphenylcyclopropenone (DCP) is a contact immunotherapeutic agent that is recommended for AA patients with more than a 50% scalp hair loss.[6] A previous investigation found that DCP induced allergic contact dermatitis, which reduced the T-cell immune-mediated reaction at the hair bulb, and induced perifollicular lymphocyte apoptosis, which lowered the proportion of CD4/CD8 lymphocytes in the peribulbar area.[7] Success rates ranging from 6% to 85% have been reported for DCP treatment of AT and AU.[89]

Anthralin (also called dithranol) is another immunomodulator drug that is used to treat AT and AU. Studies found that anthralin induced hair growth by inhibiting pro-inflammatory cytokines that cause perifollicular inflammation, such as tumor necrosis factor-α and interferon-γ.[1011] One investigation observed that topical 0.1% anthralin was effective for restoring hair loss in AA mice.[11] Fiedler-Weiss et al. reported that 25% of AA patients responded to treatment and that 18% had cosmetically good results after being treated with 0.5%–1% anthralin.[12] The combination of topical 5% minoxidil and 0.5% anthralin was reported to be effective in 11% of severe, treatment-resistant AA patients after 6 months of treatment.[13]

Chronic extensive AA is partially characterized by a resistance to single modalities of treatment. Given that the mechanisms of action of DCP and anthralin are different, the combination of these two agents may demonstrate a synergistic effect in the treatment of AT and AU. Accordingly, the aim of this study was to compare the efficacy of a combination therapy of topical DCP and topical 0.5% anthralin with that of topical DCP alone for the treatment of chronic extensive AA. The secondary objective was to compare the side effects of a combination of DCP and 0.5% anthralin with those of DCP alone.

MATERIALS AND METHODS

This split-scalp, double-blind, controlled study was conducted at the department of dermatology in a tertiary hospital in Thailand. The protocol for this study was approved by the Institutional Review Board and was registered with the Thai Clinical Trials Registry.

Patient selection

Patients aged ≥18 years with chronic severe AA (>50% hair loss), AT, or AU were enrolled. All patients were required to discontinue any treatments at least 4 weeks before the study treatment protocol commenced. Patients were excluded if they had other active skin diseases at the scalp, had received systemic immunosuppressive or corticosteroid treatment during the preceding 6 months, or had a history of resistance to DCP, also excluded were female patients who were pregnant, planning to become pregnant, or lactating. Written informed consent was obtained from all patients before their inclusion.

Experimental design

A dermatologist clinically examined each patient's scalp hair, eyebrows, eyelashes, body hair, and nails. Signs of systemic diseases that are associated with AA, such as thyroid disease (exophthalmos and pretibial myxedema) and anemia, were also evaluated. Skin biopsies were performed in all patients to confirm diagnoses.

At their first visit, the patients were sensitized with a 2% DCP solution at the vertex of the scalp (area: 9 cm2). Following the 2 weeks of sensitization, a dermatologist treated all patients at weekly intervals with a 0.0001% DCP solution on both sides of the scalp. The DCP was applied and left on the scalp for 48 h, then washed off. The concentration of DCP was gradually increased monthly. It was titrated to a maximum of 1%, or until a mild eczematous reaction was apparent for at least 48 h after a DCP application. The concentration inducing the eczematous reaction was continued weekly for the remainder of the study period. The DCP concentration was reduced if there was excessive dermatitis within 48 h of a DCP application.

For the next 3 days after a DCP application, all patients were treated with a once-daily application of 0.5% anthralin in petrolatum on one side of the scalp and a cream base on the other side of the scalp for 6 months. Anthralin and a cream base were applied at bedtime and left on overnight. The sides of the scalp upon which the anthralin and the cream base were to be applied were randomly determined by a third party. The anthralin and the cream base were filled into separate tubes that were labeled “left” or “right.” The labeling depended on the sides of the scalp that tubes were to be used on by individual patients. The packaging of the tubes of anthralin and cream base was similar in shape and color. The trial codes were revealed only after data analysis. Color digital images were taken of each subject in the same position at each clinical visit.

Efficacy assessment

The severity of AA and clinical responses was assessed at baseline and then monthly for 6 months, using the Severity of Alopecia Tool (SALT) score.[14] The scalp was divided into four areas: right side (18%), left side (18%), vertex (40%), and posterior (24%). The percentage of hair loss in each area was multiplied by the percentage of that area of the scalp. The total SALT score represents the sum of all areas of the scalp. The total score ranges from 0 to 100 for the entire scalp and 0–50 for half of the scalp (midline division). Patients with greater than a 75% hair regrowth after treatment were considered to have a cosmetically acceptable outcome. The side effects from DCP or DCP plus 0.5% anthralin were evaluated by a dermatologist at each follow-up visit. Prolonged dermatitis (more than 48 h) was defined as a side effect of the treatment.

Statistical analysis

Data were analyzed using PASW Statistics for Windows (version 18; SPSS Inc., Chicago, IL, USA). Descriptive statistics are presented as frequency and percentage, mean ± standard deviation (SD), or median (minimum, maximum). Changes in the severity scores of the groups from baseline were compared using a paired t-test for symmetrically distributed data and the Wilcoxon signed-rank test for asymmetrically distributed data. The Chi-squared test was used to compare the number of adverse events occurring in each group after the commencement of treatment. P < 0.05 was considered statistically significant.

RESULTS

A total of ten patients were enrolled, seven (70%) of whom were female. The mean age was 35.5 ± 12.8 years (range: 19–57). The baseline demographic and clinical data are listed in Table 1. Seven (70%) patients were diagnosed with AU, 2 (20%) with severe AA, and 1 (10%) with AT. The median disease duration was 3.5 years (range: 0.08–20.0). Eight patients completed the study. Two patients withdrew from the study. One developed a severe reaction after DCP sensitization (n = 1). The second patient developed severe dermatitis after an increase in the DCP concentration, with the severity of the disease progressing from chronic extensive AA to AT (n = 1).

Table 1

Demographic and clinical characteristics of the study population

Characteristics	n=10
Gender, n (%)
Male	3 (30.0)
Female	7 (70.0)
Age (years), mean±SD	35.5±12.8
Duration of disease (years), median (minimum-maximum)	3.6 (0.08-20)
Type, n (%)
Severe alopecia areata	2 (20.0)
Alopecia totalis	1 (10.0)
Alopecia universalis	7 (70.0)

SD - Standard deviation

Of the eight patients with chronic extensive AA, 4 (50%) had hair regrowth on both sides of their scalps after treatment with DCP alone and with DCP plus 0.5% anthralin. One patient with severe AA had 100% hair regrowth on one side of her scalp after 3 months of treatment with DCP and 100% hair regrowth on the other side of her scalp after 4 months of treatment with DCP plus 0.5% anthralin [Figure 1]. Another AT patient had 50% hair regrowth on the combination-treatment side and 30% hair regrowth on the DCP-alone side after 6 months of treatment. As to our AU patients, two patients had ≤10% hair regrowth after treatment, while four patients failed to respond to either treatment. Some gray villus hair was observed in three unresponsive AU patients at the combination-treatment side of the scalp.

Figure 1

Results of treatment for a chronic extensive alopecia areata patient, with 100% hair regrowth after 3 months of treatment with diphenylcyclopropenone only (left side of scalp), and after 4 months of treatment with diphenylcyclopropenone and 0.5% anthralin (right side of scalp)

The overall mean SALT scores at baseline were 47.1 ± 5.5 (range: 36.1–50) for the DCP plus 0.5% anthralin-treated site and 47.3 ± 5.1 (range: 37.8–50) for the DCP-alone-treated site. After 6 months of treatment, the mean SALT scores decreased to 38.62 ± 18.2 for the combination-treatment site and 40.7 ± 17.3 for the DCP-alone site. However, the difference in the improvements in the SALT scores achieved by the treatments was not statistically significant [P = 0.59; Figure 2].

Figure 2

Severity of Alopecia Tool scores of both treatment groups at baseline and monthly after the start of treatment. *The difference in the Severity of Alopecia Tool scores of the groups at 6 months was not statistically significant (P = 0.59). DCP – Diphenylcyclopropenone

Regarding the side effects, one patient had a severe reaction after DCP sensitization. Another reported severe dermatitis, presenting with crusting, dryness, and severe pruritus on both sides of the scalp after an increase in the DCP concentration. Although eight patients reported temporary hyperpigmentation on the combination-treatment site, no hyperpigmentation was observed at the DCP-alone site of any patient (P < 0.001). DCP plus 0.5% anthralin caused significantly more excessive dermatitis than DCP alone (7 patients vs. 2 patients; P = 0.02; Table 2). Localized bullous eruptions were reported for one patient on the combination-treatment side of the scalp. Patients with excessive dermatitis were treated with mild topical corticosteroids. Cervical lymphadenopathy was noted in one patient.

Table 2

Comparison of the adverse effects of the treatment regimens

	DCP plus 0.5% anthralin, n (%)	DCP, n (%)	P
Dryness
Yes	6 (66.7)	4 (44.4)	0.34
No	3 (33.3)	5 (55.6)
Excessive dermatitis
Yes	7 (77.8)	2 (22.2)	0.02*
No	3 (22.2)	8 (77.8)
Pruritus
Yes	4 (44.4)	3 (33.3)	0.63
No	5 (55.6)	6 (66.7)
Folliculitis
Yes	2 (22.2)	0	0.13
No	7 (77.8)	9 (100)
Hyperpigmentation
Yes	8 (88.9)	0	<0.001*
No	1 (11.1)	9 (100)

*P<0.05 indicates statistical significance. DCP - Diphenylcyclopropenone

DISCUSSION

Topical immunotherapy with DCP is recommended and widely used for AT and AU treatment.[6] Several studies reported the effectiveness of DCP for AT and AU; however, the hair-regrowth rates attributed to DCP have been variable. The rate for regrowth of greater than 50% has varied markedly between studies, ranging from 15.4% to 71% of DCP-treated AU and AT patients.[15161718] Based on the average hair-regrowth rate, Leong et al. reported a low mean regrowth of 26% at the 4-year follow-up visit of AT and AU patients.[19] A systematic review reported an average response rate of 47.7% for AT and AU patients treated with DCP.[20] Recently, a systematic review and meta-analysis revealed an average hair-regrowth rate of 51.6% for AT and AU patients.[21] A <10% chance of a full recovery by AT and AU patients was also reported.[1]

In the current investigation, patients with severe AA and AT had better outcomes than those with AU. DCP showed a satisfactory outcome in one severe AA patient, as demonstrated by 100% hair regrowth after 3 months of DCP treatment. One AT patient had 30% hair regrowth after DCP treatment. However, the mean hair-regrowth rate in six AU patients treated with DCP was only 33.3%, which was in line with previous studies.[192021] The difference in treatment responses can be explained by variations in the study designs, different treatment regimens, and different baseline characteristics (disease severity, disease duration, and disease onset).

Combination therapies are recommended for treatment-resistant AT and AU.[22] The combination of DCP and anthralin may have synergistic effects due to their different mechanisms of action. Durdu et al. reported that the combination of DCP and 0.5% anthralin was more effective than treatment with DCP-alone. In their study, 88% of patients had at least 50% hair regrowth after 30 weeks of treatment.[17] Nasimi et al. retrospectively reviewed a series of 32 cases of DCP-nonresponsive AA patients who were treated with DCP and anthralin. Those researchers reported a mean hair-regrowth rate of 41%. They also concluded that the combination therapy was effective in treating nonresponsive AA patients and had no serious side effects.[23] Kagami et al. reported a good efficacy of combination therapy of DCP and anthralin in four patients with refractory AA. Specifically, multifocal patches of AA were more responsive to the treatment than AT. The patients with multifocal patches of AA had complete and partial hair regrowth, whereas no hair regrowth was observed in the AT patients.[24] In contrast, Ibrahim et al. reported that patients treated with DCP alone had a significantly higher complete hair-regrowth rate than the patients who received the combination therapy of DCP and anthralin (62.5% vs. 18.2%; P = 0.04).[25] In our study, the combination therapy did not show a better outcome than treatment with DCP alone. Although the mean overall SALT scores of both groups improved between baseline and 6 months, the difference in the degrees of improvement was not statistically significant. This is probably due to the short follow-up period relative to those used by other studies.[172324] Further studies with extended follow-up periods are required to elucidate the efficacy of the combination therapy. A higher treatment response rate might be achieved by using a longer treatment duration.[23]

In a previous study, the side effects – superficial folliculitis and hyperpigmentation – were reported more frequently for the combination-therapy group.[17] In addition, members of that group reported more severe levels of irritation and higher degrees of staining of the skin, hair, and clothes.[25] Similarly, hyperpigmentation and excessive dermatitis were significantly more common among the patients receiving combination therapy. Although the contact time for the anthralin in this study was longer than that of earlier studies,[1723] no other adverse effects were reported. To diminish the side effects, a decrease in the duration of the administration of anthralin may prove helpful. The higher incidence of side effects in the combination-therapy group might be attributable to an enhanced irritation effect from the combined DCP and anthralin. Moreover, both DCP and anthralin are photosensitive agents. Given that Thailand is a tropical country, high sunlight exposure may therefore be another reason for the higher number of adverse events. Photoprotection is therefore recommended during treatment.

As this was a pilot study, there were a small number of participants. This is the key limitation of the research. Another notable limitation is the short duration of treatment. Given the recalcitrant nature of chronic extensive AA, it is possible that some patients could respond to treatment at more than 6 months after the start of treatment.[2326]

CONCLUSIONS

The combination of DCP and 0.5% anthralin was not superior to DCP alone for the treatment of chronic extensive AA. An increase in side effects – excessive dermatitis and hyperpigmentation – was observed for the combination-treatment group. An additional randomized controlled study with more participants and longer treatment duration is needed to elucidate the comparative efficacy of the combination treatment.

Financial support and sponsorship

This study is supported by Siriraj Research Fund, Faculty of Medicine Siriraj Hospital, Mahidol University

Conflicts of interest

There are no conflicts of interest.