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ORIGINAL ARTICLE
Year : 2022 | Volume
: 40
| Issue : 4 | Page : 214-221
Topical diphenylcyclopropenone in the treatment of alopecia areata: A 10-year follow-up of 86 cases in a single center
Chang-Ming Huang1, Tsen-Fang Tsai2
1 Department of Dermatology, National Taiwan University Hospital, Taipei, Taiwan
2 Department of Dermatology, National Taiwan University Hospital; Department of Dermatology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
Correspondence Address:
Prof. Tsen-Fang Tsai
Department of Dermatology, National Taiwan University Hospital, No. 7, Chung Shan S. Road, Taipei 10048
Taiwan
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/1027-8117.360448
Background: Diphenylcyclopropenone (DPCP) is a topical contact allergen used for contact immunotherapy in alopecia areata (AA). Objectives: We aimed to evaluate the treatment effectiveness and prognostic factors in Taiwanese patients with AA treated with topical DPCP. Methods: We performed a retrospective study of all consecutive patients with AA affecting more than 10% of scalp area treated with topical DPCP for more than 90 days. Results: Eighty-six patients were assessed in the study. The greatest hair regrowth percentages of 0%, 1%–25%, 26%–50%, 51%–75%, and 76%–100% were 26.7% (23/86), 7.0% (6/86), 2.3% (2/86), 10.5% (9/86), and 53.5% (46/86) of patients, respectively. 32.6% (28/86) of patients achieved near-complete remission (with or without maintenance DPCP therapy), defined as more than 90% sustainable hair regrowth. Positive prognostic factors include older age of onset, shorter duration of AA before DPCP treatment, less severity of hair loss, and no nonscalp hair loss. Multivariate logistic regression analysis showed that more than a 2-year duration of AA before DPCP treatment (P = 0.015) and more than 90% of hair loss (P = 0.032) had a poorer treatment outcome. Factors including eczematous sensitization reaction, history of atopy, adverse reactions, or concentrations of DPCP do not predict treatment effectiveness. Pigmentary change may cause cosmetic concerns in Chinese ethnicity. Conclusion: Topical DPCP is effective for AA. Various factors were associated with the clinical outcomes. Monitoring the possible adverse events is warranted.
Keywords: Alopecia areata, alopecia totalis, alopecia universalis, contact dermatitis, diphenylcyclopropenone, topical immunotherapy
Alopecia areata (AA) is an immune-mediated disorder that results in nonscarring hair loss. Severe AA can be subclassified into alopecia totalis and alopecia universalis, affecting the whole scalp and full body hair, respectively.[1] Change of appearance results in impaired psychosocial function and deterioration in the quality of life significantly.[2] Treatment options of AA include topical, intralesional or systemic corticosteroids, topical minoxidil, contact immunotherapy, Janus kinase inhibitors, and other modalities.[1],[3] Patchy AA is reported to exhibit a better prognosis with a high possibility of spontaneous remission than alopecia totalis and alopecia universalis.[4]
Contact immunotherapy, or topical immunotherapy, acts through the induction and periodic elicitation of allergic contact dermatitis by topical contact allergens.[5] An ideal therapeutic topical sensitizer should have little potential of inducing cross-sensitization to other substances in addition to being safe and absent from the natural environment.[6] Diphenylcyclopropenone (DPCP) and squaric acid dibutyl ester (SADBE) are frequently used contact allergens in AA treatment. At present, DPCP is the preferred contact allergen because it is more stable in acetone and is relatively cheaper than SADBE.[7],[8] In contrast, dinitrochlorobenzene, another contact allergen used previously, has been abandoned due to its mutagenicity.[6],[9] DPCP has no cross-sensitivity to other chemicals except its precursor.[10] It is nonmutagenic in the Ames assay at 50 and 100 μ g/mL concentrations.[11]
The mechanism of action of contact immunotherapy in AA is still unclear. Allergic contact dermatitis rather than irritant is necessary for the regrowth of hair.[12] Antigenic competition with the causative autoantigen has been hypothesized. Introducing a second antigen providing an alternative immune target can initiate a new infiltrate containing T-regulatory lymphocytes to decrease follicular immune reaction.[6] Cytokine alteration has also been proposed as another possible mechanism.[13],[14] The therapeutic outcomes and prognostic factors of topical DPCP in AA varied widely in the literature.[15],[16],[17],[18] There are only a few Chinese reports of DPCP in AA treatment.[19],[20] No Taiwanese data was previously reported. This retrospective study aimed to summarize the treatment response, adverse effects, and prognostic factors of DPCP treatment in AA patients, especially Taiwanese.
MethodsStudy design
We performed a single-center, retrospective observational study to assess the treatment effectiveness and adverse events of topical DPCP in AA treatment from January 2011 to September 2020 in the dermatologic outpatient clinic at National Taiwan University Hospital. This study was approved by the Research Ethics Committee of National Taiwan University Hospital (202001039RINB).
Study subjects
Patients with AA treated with topical DPCP for more than 90 days between January 2011 and September 2020 were included. These patients fulfilled the following criteria: failing other managements for AA, such as oral prednisolone, intralesional steroid, topical minoxidil, excimer, and Fraxel laser, or present with >50% scalp involvement. The treatment algorithm was consistent with the recommendation in some consensus.[3] We only included patients who received DPCP treatment for more than 90 days because previous studies found that the first regrowth of hair is noted after 3 months of treatment.[14] Patients with <10% hair loss were excluded. Data were obtained from medical records, pictures, and telephone interviews, including demographics, initial hair loss severity, DPCP concentration, treatment effectiveness, and adverse events.
Preparation of diphenylcyclopropenone
We used DPCP from the company Sigma-Aldrich to prepare the different concentrations of DPCP solution. DPCP was made up in acetone. The concentrations used in the study were mainly 0.0001%, 0.0003%, 0.001%, 0.003%, 0.01%, 0.03%, 0.1%, 0.3%, 1%, and 2%. DPCP solution was stored in a cupboard away from sunlight. The preparation of the DPCP solution was under the supervision of the department of pharmacy of the hospital.
Treatment protocol
The treatment of topical DPCP for AA comprises three parts: sensitization, treatment, and maintenance. Sensitization was performed by occlusion of 2% DPCP on a coin-sized area on the arm for 24–48 h. The first DPCP treatment started about 2 weeks after 2% DPCP sensitization. We applied topical DPCP to the entire scalp once every week during the treatment phase. The DPCP concentration was initiated from a lower one (e.g., 0.0001% DPCP) and increased stepwise until mild erythema and pruritus occurred. The concentrations of DPCP solution used in this study were mainly 0.0001%, 0.0003%, 0.001%, 0.003%, 0.01%, 0.03%, 0.1%, 0.3%, 1%, and 2%. Patients were also advised not to wash the scalp for 24–48 h. After satisfactory hair regrowth (e.g., >90% hair regrowth) and negative hair pull test, the treatment intervals were gradually prolonged to once every 4 weeks. This phase of DPCP management is also known as maintenance therapy. Patients could adjust the treatment interval or even withdraw from the treatment according to the disease status. Overall, reasons for treatment cessation include intolerable adverse events, unsatisfactory response after 20–30 weeks, near-complete regrowth, or other personal reasons.
Outcomes measures
We defined treatment outcomes according to the greatest hair regrowth percentage and sustainability of hair regrowth. Hair regrowth percentage was divided into the following groups: 0% (no regrowth), 1%–25%, 26%–50%, 51%–75%, and 76%–100%. We further defined near-complete remission as more than 90% sustainable hair regrowth. Sustainable hair regrowth means the degree of hair regrowth can be maintained with or without DPCP maintenance therapy for more than 3 months. The treatment outcome was collected from the medical records or photo records.
We defined steady concentration as the same DPCP concentration applied to the patients in two consecutive therapies. Initial, final, and highest steady concentrations were determined throughout the treatment and maintenance phase.
Statistical analysis
Descriptive statistics were used to summarize the patients' demographics and clinical characteristics. The between-group comparisons were performed using the Chi-square tests and Fisher's exact tests for categorical data and the Mann–Whitney U test for numerical variables. Multivariate logistic regression analysis was applied to confirm the associations. Concentration changes throughout the treatment course were compared by Wilcoxon signed–rank test. All P values were from 2-sided tests, and results were deemed statistically significant at P < 0.05. Analyses were performed using statistical product and service solutions statistics version 18 (IBM Corp. Armonk, NY, USA).
ResultsStudy subjects
One hundred and four patients who received DPCP treatment for more than 90 days between January 2011 and September 2020 were included in this study. A total of 12 cases were excluded due to a lack of detailed data. Six patients were further excluded due to <10% scalp involvement. Eighty-six patients were eligible for the analysis.
Patient characteristics
The median age at onset of AA patients was 25 years (interquartile range [IQR]: 15–36). The patients consisted of 25 (29.1%) men and 61 (70.9%) women. The median time between disease onset and initiation of DPCP treatment was 2 years (IQR: 0–9). The median DPCP treatment duration was one year (IQR: 0–2). The median time to hair regrowth after DPCP treatment was 3 months (IQR: 2–6). 20 (23.3%) patients had a history of atopy, including allergic rhinitis, asthma, or atopic dermatitis, while 6 (7.0%) patients had atopic dermatitis [Table 1]. Most patients (80/86, 93%) had undergone prior treatments for AA with unsatisfactory response, including topical steroids (14/86, 16.3%), intralesional steroids (47/86, 54.7%), systemic steroids (38/86, 44.2), topical minoxidil (12/86, 14.0%), cryotherapy (7/86, 8.1%), Fraxel laser (5/86, 5.8%), light therapy (excimer or low level laser therapy) (8/86, 9.3%), Chinese medicine (13/86, 15.1%), and other treatment (methotrexate (1/86, 1.2%), azathioprine (1/86, 1.2%)). The severity of hair loss is shown in [Table 1].
Treatment response
The greatest hair regrowth percentages of 0%, 1%–25%, 26%–50%, 51%–75%, and 76%–100% were 26.7% (23/86), 7.0% (6/86), 2.3% (2/86), 10.5% (9/86), and 53.5% (46/86) of all patients, respectively. 32.6% (28/86) of patients achieved near-complete remission (with or without maintenance DPCP therapy) in all patients and 17.1% (7/41) in alopecia totalis or alopecia universalis patients [Table 2]. Four patients who had recurrent episodes of AA after complete remission without maintenance DPCP therapy for 1–8 years chose to receive further DPCP treatment. The following DPCP treatment was only effective in 2 (50.0%) patients. Five of our patients who had a poor response or partial response to DPCP received tofacitinib 10 mg/day, a JAK inhibitor, afterward. Four (80.0%) of them exhibited cosmetically acceptable hair regrowth (more than 90% hair regrowth).
Table 2: Treatment response and adverse events of diphenylcyclopropenone treatment in alopecia areata patientsDiphenylcyclopropenone sensitization reaction
All patients had sensitization initially. Twenty (29.9%) patients reported no reaction, 29 (43.3%) patients developed local erythema, and 18 (26.9%) patients resulted in blistering [Table 1]. Sensitization reaction was not recorded in the medical chart in 19 patients. A Chi-square test of independence showed no significant association between eczematous sensitization reaction (erythema or blistering) and treatment effect [Table 3].
Table 3: Prognostic factors of diphenylcyclopropenone treatment in alopecia areata patientsPrognostic factors
Statistical analyses were performed to examine the relationship between potential prognostic factors and treatment effectiveness (near-complete remission or not). Age of onset, duration of AA before DPCP treatment, severity of hair loss, nonscalp hair loss, eyebrow loss, eyelash loss, and pubic hair loss were predictive factors for hair regrowth. The definition of nonscalp hair loss is any hair loss from eyebrow, eyelash, axillary hair, or pubic hair. By Mann–Whitney U test, older age of onset (P = 0.037), shorter duration of AA before DPCP treatment (P = 0.025), and less severity of hair loss (P = 0.020) predicted the better extent of hair regrowth. By Chi-square test, positive predictive factors for hair regrowth included duration of AA before DPCP treatment < 2 years (P = 0.001), severity of hair loss < 90% (P = 0.002), no nonscalp hair loss (P = 0.012), no eyebrow loss (P = 0.001), no eyelash loss (P = 0.024), and no pubic hair loss (P = 0.034). Results of sex, age of onset after 20 years old, and atopy did not reach statistical significance by Chi-square test.
Multivariate logistic regression analysis showed that more than a 2-year duration of AA before DPCP treatment (P = 0.015) and more than 90% of hair loss (P = 0.032) had a poorer treatment outcome [Table 4].
Table 4: The association between near-complete remission and prognostic factors using multivariate logistic regression analysis†Adverse events
Pruritus (95.3%) and eczema (90.7%) were noted in most patients. Other adverse events observed among AA patients treated with DPCP included severe eczema on the scalp leading to blistering (51.2%), erosions (30.2%), urticaria (15.1%), lymphadenopathy (24.4%), hyperpigmentation (15.1%), hypopigmentation (10.5%), and allergic reaction other than scalp (11.6%) [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d, [Figure 1]e, [Figure 1]f and [Table 2]. However, a Chi-square test of independence showed no significant association between adverse events and treatment effects [Table 3]. Hypopigmentation was either due to postinflammatory hypopigmentation or vitiligo, which was diagnosed by clinical presentation. Three patients had hypopigmentation on the scalp, one on the left arm sensitization site, three on the body site without direct contact with DPCP, and two on both scalp and other body parts [Figure 1]d, [Figure 1]e, [Figure 1]f. Among the nine patients, five patients had near-complete remission of AA, with three of them under maintenance therapy. Dyschromia in confetti, a pigmentary disturbance consisting of a combination of hyperpigmentation and hypopigmentation, was previously described in topical immunotherapy.[21],[22] However, we did not observe this pattern of pigmentary change.
Figure 1: The adverse events of topical diphenylcyclopropenone in treatment of alopecia areata. (a) Tense blisters developed on the scalp. (b and c) Hyperpigmentation manifested on the forehead, possibly due to dripping of diphenylcyclopropenone solution from the scalp, habitual wig-wearing, or hat-wearing. (d) Vitiligo developed from the site of diphenylcyclopropenone sensitization with an extension. (e and f) An alopecia universalis patient with near-total hair loss before (e) and after three months of diphenylcyclopropenone treatment (f). She achieved nearly full hair regrowth with new-onset vitiligo from the scalp to the nape after three months of diphenylcyclopropenone treatment.Diphenylcyclopropenone concentration and tolerance
We defined steady concentration as the same DPCP concentration applied to the patients in two consecutive therapies. The Wilcoxon signed-rank test found the final steady concentration higher than the initial steady concentration (P < 0.001). Most patients' final steady concentration (37.2%) was in the range between 0.01% and 0.1% [Figure 2]. There was no significant difference in treatment response between different initial, final, or highest steady concentrations of DPCP [Table 3].
Figure 2: Final steady concentration distribution. Most patients' final steady concentration (37.2%) was in the range between 0.01% and 0.1%. Discussion Topical DPCP immunotherapy has been used to treat AA since 1983.[23] Several studies that evaluated the effectiveness of topical DPCP treatment for AA showed variable results. In our study, 64.0% of all patients had the greatest regrowth percentage over 50%, and 32.6% achieved near-complete remission. 53.7% of alopecia totalis and alopecia universalis patients had the greatest regrowth percentage over 50%, and 17.1% achieved near-complete remission [Table 2]. Two systematic reviews have revealed that DPCP is effective in AA, with an average response rate of 53.75% to 65.5%.[24],[25] In the alopecia totalis and universalis subgroup, the average response rate of 47.65% to 54.5% is concluded in these systematic reviews.[24],[25] The effect of racial differences on DPCP effectiveness is unknown. The difference in effectiveness between each study can be partially attributed to the lack of standardized criteria for therapeutic regrowth in each study. For example, some studies adopted the MacDonald Hull and Norris grading, which defined effectiveness by no regrowth, vellus hair, sparse, patchy, or whole scalp terminal hair.[26] Others used a 'cosmetically acceptable' measure as their endpoint.[18] Still others adopted modified global assessment criteria based on their scalp surface area improvement compared with the baseline into quartile ranges.[27] We used 25%, 50%, and 75% as the cutoff point for the assessment. We further apply 90% cutoff point to define near-complete remission. In our opinion, more than 90% hair regrowth better correlates with the patient's perception of a good response. Similar cutoff points are also adopted in many previous studies.[20],[28],[29],[30] A standardized outcome evaluation would enable future studies to be more comparable.
Several previous studies found favorable prognostic factors similar to ours, including older age of onset,[17],[31] shorter duration of AA before DPCP treatment,[15],[16],[31],[32] and less severity of hair loss.[15],[16],[17] History of atopy did not significantly influence the treatment response in our series.[16],[17],[18] Previous studies regarded alopecia universalis[18],[31] as a poorer prognostic factor. Our study separately analyzed the nonscalp hair loss because nonscalp hair loss is not restricted to patients with complete hair loss on the scalp. We found that nonscalp hair loss predicts a poorer treatment response. We further analyzed the particular area of nonscalp hair loss and found that eyebrow loss, eyelash loss, and pubic hair loss indicate more inadequate treatment response. However, axillary hair loss did not achieve statistical significance (P = 0.072). Further investigation is needed to determine whether this is true or merely a result of the small sample size. We also performed a multivariate logistic regression analysis, which showed that more than a 2-year duration of AA before DPCP treatment (P = 0.015) and more than 90% of hair loss (P = 0.032) had a poorer treatment outcome [Table 4]. Other factors did not reach statistical significance in multivariate logistic regression analysis.
Many adverse events have been reported due to the use of DPCP. In our series, pruritus and eczema happened in nearly all patients. It is not surprising since pruritus and adequate eczema are the expected endpoints of each treatment. Severe eczema on the scalp leading to blistering (51.2%) or erosions (30.2%) were also frequent adverse events, while severe eczema was 20.8% to 30.8% in the previous meta-analysis.[24],[25] Severe eczema can be alleviated by topical or systemic steroids and prevented through careful concentration titration. Other adverse events in our series were urticaria (15.1%), lymphadenopathy (24.4%), hyperpigmentation (15.1%), hypopigmentation (10.5%), and allergic reaction other than scalp (11.6%). Besides the suffering of discomfort, patients are concerned about whether the major adverse events affect clinical response. According to our cohort and the previous study, adverse events did not influence prognosis.[17]
Special concerns should be taken for the pigmentary change in patients with skin colors compared to the Western population. Hyperpigmentation was reported in 36.4% to 45.0% of Chinese patients in previous studies, while it was 14.1% in our series.[19],[20] In comparison to the reported frequency in meta-analyses, hyperpigmentation accounts for only 6.8% to 12.7% in patients of all ethnicities.[24],[25] Hyperpigmentation could be evident on the forehead, probably caused by dripping of DPCP solution from the scalp, habitual wig-wearing, or hat-wearing [Figure 1]b and [Figure 1]c. Although not noted in the other Chinese cohorts,[19],[20] the much higher hypopigmentation rate (10.5%) in our patients than in the meta-analysis of all ethnicities (1.6%) also warrants the clinician's attention.[24]
AA and vitiligo share similarities in their pathogenesis. The two diseases manifest autoimmune attacks of specific skin components, the hair unit and the melanocyte, respectively.[33] Interferon gamma (IFN-γ)-driven immune response is the common key immune signaling pathway in the two diseases involving IFN-γ, IFN-γ-induced chemokines, and cytotoxic CD8+ T cells.[33],[34] These two diseases also coexist more frequently. 3%–8% prevalence of vitiligo in AA patients was reported, which was higher than 1% in the general population.[35] DPCP application results in unmasking vitiligo in these susceptible individuals.[36],[37] Two mechanisms have been postulated to explain how DPCP induces vitiligo. Vitiligo may be induced by the Koebner phenomenon from repeated inflammation of contact dermatitis. Vitiligo may also be caused by the direct cytotoxic effect of the contact sensitizer on melanocytes following systemic absorption, particularly when distant sites are involved.[37],[38],[39],[40] DPCP-induced vitiligo was not limited to patients of AA. There was a report of passive transfer of DPCP to susceptible partners.[41] DPCP-induced vitiligo during treatment of viral warts was documented but rare, perhaps because such individuals are intrinsically less vulnerable to vitiligo.[42] Treatment for this form of vitiligo includes discontinuation of DPCP, topical glucocorticoids, or phototherapy narrow-band ultraviolet B phototherapy.[39],[42] Janus kinase inhibitors, which are effective in treating both AA and vitiligo, may be beneficial in these patients.[33]
Some authors suggested that those who require higher DPCP concentration to induce eczematous treatment reaction experienced a more inadequate treatment response.[17],[43] However, we did not find an association between DPCP concentration and treatment response in our series, considering the initial, final, and highest steady concentrations. Our protocol titrated DPCP concentration to a specific concentration that induces a mild eczematous response lasting about 24 h. We suppose the adequate local inflammatory reaction determines the treatment effectiveness rather than the DPCP concentration. This concept is compatible with the finding of Lamb et al.[16]
Tolerance is a state of unresponsiveness of the immune system to allergens. Tolerance could be demonstrated by the greater final steady concentration than the initial steady concentration in our patients (P < 0.001). This phenomenon indicates that increased DPCP concentration is necessary to induce a similar eczematous reaction throughout the treatment course. Tolerance could also manifest in those who failed the treatment after the concentration reached 2%, resulting in the loss of regrown hair.[32],[44] The disappearance of reactivity to the contact allergen occurred in 5.8% of patients in the literature, while 2 (2.3%) patients in our study had similar scenarios.[45] A previous report found that SADBE could be effective in some patients who acquired tolerance to DPCP.[32]
This study's limitations include the lack of a control group, the retrospective study design, and the small sample size. Furthermore, the study did not apply a more specific scoring system like the severity of alopecia tool for the therapeutic response.[27]
ConclusionDPCP is an effective treatment for AA, but close monitoring of adverse events is warranted. Better prognostic factors include older age of onset, shorter duration of AA before DPCP treatment, less severity of hair loss, and no nonscalp hair loss. Multivariate logistic regression analysis showed that more than a 2-year duration of AA before DPCP treatment (P = 0.015) and more than 90% of hair loss (P = 0.032) had a poorer treatment outcome. Tolerance is a frequently observed phenomenon and may cause treatment failure in a few patients. Pigmentary change, including hyperpigmentation or hypopigmentation, could concern Chinese ethnicity.
Financial support and sponsorship
Nil.
Conflicts of interest
Prof. Tsen-Fang Tsai, an editorial board member at Dermatologica Sinica, had no role in the peer review process of or decision to publish this article. Prof. Tsen-Fang Tsai has conducted clinical trials or received honoraria for serving as a consultant for Abbvie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli-Lilly, Galderma, GSK, Janssen-Cilag, Leo Pharma, Merck Sharp and Dohme, Novartis International AG, Pfizer Inc., and UCB Pharma. Dr. Chang-Ming Huang has no conflict of interest to declare.
References
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