Alopecia areata (AA) is a highly unpredictable, autoimmune skin disease resulting in loss of scalp and body hair. It affects ∼1.7% of the overall population 1. Although it is medically benign, it can cause tremendous emotional and psychosocial stress in affected patients and their families 2.
The exact pathogenesis of AA is yet to be established; the most widely accepted hypothesis is that AA is a T-cell-mediated autoimmune condition 2,3. It may involve the entire scalp (alopecia totalis) or complete body hair [alopecia universalis (AU)] 4,5.
Treatment for AA is generally unsatisfactory. A number of treatments can induce hair growth but none have been shown to alter the course of the disease 6,7.
Phototherapy, which is the exposure to UV radiation for therapeutic use, has been investigated in the treatment of AA 8. It can be administered in various ways, including photochemotherapy, broadband and narrowband UVB phototherapy (NB-UVB), UVA1, and photodynamic therapy 9,10.
Although NB-UVB phototherapy is a well-established treatment in many dermatoses, it was investigated in AA treatment with encouraging results but with little documented evidence of its efficacy 11,12.
Psoralen photochemotherapy (PUVA) is the combined use of psoralen and UVA radiation 8. The concerns about phototoxicity and possible carcinogenicity limit the long-term use of oral PUVA and have led to the introduction of other photochemotherapeutic agents such as khellin with low genotoxicity and no long-term side effects and phototoxic skin erythematic responses 11,13. Khellin photochemotherapy (KUVA) has been studied as a treatment for AA with encouraging results in terms of a high success rate and minimal side effects 14,15.
Therefore, we aimed at comparing the efficacy of NB-UVB phototherapy with KUVA photochemotherapy as two modalities in the treatment of recalcitrant AA.
Patients and methods
A total of 38 patients with AA of different clinical forms who consulted or referred to the outpatient dermatology clinic at Assiut University Hospital between May 2008 and January 2010 were included in our study.
Patients with a disease duration of more than 6 months or a rapidly progressive course of AA, regardless of the duration of the disease, were included in our study. All patients were resistant to previous topical therapies or systemic steroids, and none of them had a history of phototherapy. No concomitant treatment was administered during the period of the study. Prior treatment was stopped in all patients at least 3 months before inclusion in our study.
Pregnant and lactating women, patients who were currently experiencing significant terminal hair regrowth, and patients who had not received other treatment modalities earlier were excluded from the study.
Detailed history was taken from all patients, including age of the patient, age at onset, duration of AA, previous treatments used and their efficacy, history of associated diseases, and family history of AA.
The clinical form of AA and the baseline ‘Severity of Alopecia Tool score’ (SALT score), according to Olsen et al. 16, were determined for all patients.
To determine the SALT score, the scalp is divided into four areas, namely, the vertex – 40% (0.4) of scalp surface area; right profile of the scalp – 18% (0.18) of scalp surface area; left profile of the scalp – 18% (0.18) of scalp surface area; and posterior aspect of the scalp – 24% (0.24) of scalp surface area. The percentage of hair loss in any of these areas is the percentage hair loss multiplied by the percentage surface area of the scalp in that area. The SALT score is the sum of the percentage of hair loss in all the above-mentioned areas 16.
All patients gave their formal consent. The protocol was approved by the Ethical Committee of the Faculty of Medicine, Assiut University.
This study was carried out at the UV Unit at the Department of Dermatology, Assiut University Hospital. Photographs of the four views of the scalp were taken for each patient. In both therapeutic modalities, irradiation was administered three times weekly for 24 weeks or until complete terminal hair regrowth.
Patients were randomly divided by computer-generated random numbers into two groups. Group I (n=19) patients were treated with topical khellin on the scalp, followed by UVA irradiation (KUVA), and group II (n=19) patients were treated with NB-UVB irradiation.
Group I (KUVA group)
Nineteen patients were treated with topical 2% khellin paint (Ezalline, Multipharma Co., Cairo, Egypt) applied to the alopecic area on the scalp 30 min before UVA irradiation with an intensity of irradiation between 310 and 380 nm, with a peak emission at 365 nm (Waldmann PUVA 100; Waldmann Medizintechnik, Peter-Henlein, Germany). The starting UVA dose was 1.5 J/cm2, with increments of 0.3 J/cm2 every two sessions until a maximum dose of 8 J/cm217,18 or the effective dose (the dose at which the first regrowth of hair was observed) was reached, and was kept constant until the end of the course.
Group II (NB-UVB group)
Nineteen patients were treated with NB-UVB on the scalp. The NB-UVB source was a Waldmann (TL-01) half cabinet (Waldmann Medizintechnik). The NB-UVB output includes a spectrum of irradiation ranging between 310 and 315 nm, with a peak emission at 311 nm. Irradiation doses started at 0.24 J/cm219 and were increased by 10% every session according to the erythema response or until the maximum single dose of 4 J/cm2 had been reached 20.
Patients were assessed during every session for any side effects and were also assessed every 4 weeks by direct scalp observation and through photographs.
The treatment endpoints for our patients were either an absence of hair regrowth (either vellus or terminal) after completion of 12 weeks of therapy or the presence of a terminal full regrowth after the treatment course (24 weeks) was completed.
According to the clinical response at the treatment endpoint, the patients were classified as either treatment failures (patients who had no response after 12 weeks of therapy or only vellus hair regrowth at the end of the treatment course) or treatment responders (patients who had terminal hair regrowth).
The percentage of terminal hair regrowth based on the SALT score was calculated using the following equation:
The treatment responders were classified according to the percentage of hair regrowth into three categories, namely, excellent (hair regrowth >60%), good (hair regrowth 30–60%), and poor (hair regrowth <30%).
Patients demonstrating an improvement underwent a monthly follow-up for at least 3 months to assess the stability of hair regrowth and detect of a relapse.
All data obtained were transferred to the statistical package for the social sciences, version 13 (SPSS Inc., Chicago, Illinois, USA). Descriptive statistics used included frequency and percentage for qualitative data and mean±SD for quantitative data. The χ2-test was used for qualitative data and the student t-test for quantitative data. Pearson’s correlation was used for quantitative data in the same group. A P value of 0.05 or less was considered significant, and a P value of 0.001 or less was considered highly significant.
Demographic and clinical data of the 38 AA patients (21 male and 17 female) included in our study are summarized in Table 1.
Clinical response to KUVA therapy
The classification of patients according to the clinical response:
- Treatment responders: A total of 11 patients (57.89%) were treatment responders (Fig. 1). Among them, nine patients (47.3%) had an excellent response [six patients (31.6%) had complete hair regrowth, three (15.8%) had terminal hair regrowth >60%]; the remaining two patients (10.52%) had terminal hair regrowth less than 30% at the end of treatment course and were considered as having a poor response.
- Treatment failures: A total of eight patients (42.11%) were treatment failures. Among them, six patients (31.6%) had no signs of regrowth after 12 weeks of treatment and two patients (10.52%) had only vellus hair regrowth at the end of 24 weeks.
Clinical response to NB-UVB therapy
The classification of patients according to the clinical response:
- Treatment responders: Two patients (10.52%) were treatment responders (Fig. 2). Both patients (10.52%) had patchy type alopecia and achieved complete hair regrowth (excellent response).
- Treatment failures: A total of 17 patients (89.48%) were treatment failures. Among them, 10 patients (52.62%) had no signs of regrowth after 12 weeks of treatment and seven patients (36.86%) had only vellus hair regrowth at the end of 24 weeks.
Comparison between the clinical responses to the two therapeutic modalities among the studied groups showed that the patient response to KUVA therapy (57.89%) was statistically higher than that to NB-UVB therapy (10.52%, P<0.05). An excellent response was significantly more frequent among the KUVA group (group I, P<0.001) (Table 2).
There was no significant correlation between clinical response to both therapeutic modalities with regard to the age at onset of AA (r=0.358 for group I and 0.698 for group II, P>0.05 for both groups), the duration of AA (r=0.492 for group I and 0.427 for group II, P>0.05 for both groups), and the extent of AA (based on the SALT score) (r=0.283 for group I and 0.695 for group II, P>0.05 for both groups).
When the clinical responses in patients of both groups with SALT scores less than 50% were compared, significant differences were seen between the responders of the two groups. A significant difference was also found between the two groups with regard to SALT score greater than 50%. The frequency of the clinical response to KUVA therapy was higher among patients with SALT score less than 50 but did not reach statistical significance (Tables 3 and 4).
In group I, all clinical forms of AA, except AU, responded to KUVA therapy. In contrast, in group II, only patients with patchy AA responded to NB-UVB therapy. Both modalities of treatment were well tolerated by all patients.
The first study on KUVA therapy in the treatment of AA was carried out by Tritrungtasna et al.14, which included 10 patients with different types of AA and had encouraging results in terms of high success rates and minimal side effects.
Few studies 21 have been performed on the efficacy of NB-UVB in the treatment of AA. Krook 22 was the first to discover that the use of phototherapy with UVB light was useful in some patients with AA. Thereafter, a pilot study by Bolduc et al.10 on seven patients with extensive AA demonstrated the effectiveness of NB-UVB in the treatment of AA with minimal side effects.
In our study, KUVA therapy was more effective than NB-UVB therapy in AA patients. Our results showed that 47% of patients treated with KUVA therapy showed an excellent response to treatment; this is in agreement with the results of Tritrungtasna et al.14, who found excellent results in 50% of AA patients treated with KUVA therapy. In contrast, we found excellent results in only 10.52% of patients who were treated with NB-UVB therapy, which is less than that observed by Bolduc et al.10, who reported hair regrowth in 28% of their seven patients, and by Bayramgürler et al.12, who demonstrated that NB-UVB is not an effective treatment, with excellent results in 20% of 25 patients with AA in their retrospective study.
Although the mechanism of action of KUVA in AA is unknown, it was considered to be a modulation of the immune response, based on the concept that the mononuclear cells that surround the affected hair follicles may play a direct pathogenic role and that KUVA therapy may eradicate this inflammatory cell infiltrate 14. Furthermore, it has been shown that treatment with a contact sensitizer changes the composition and localization of the perifollicular infiltrate in humans 23,24. The localization of the inflammatory infiltrate shows a shift from peribulbar before treatment to the upper dermis after therapy. However, in human AA, the CD4 : CD8 ratio changed from 4 : 1 before therapy to 1 : 1 after therapy. Hoffmann et al. 25 demonstrated that after treatment with a contact sensitizer, the mRNA-expression of IFN-γ is reduced, whereas the expression of IL-10 is increased. Whether this is due to a Th1–Th2 shift or whether it is caused by the introduction of regulatory T cells with a type 2 cytokine profile is unclear.
Furthermore, immunohistochemical studies have shown that treatment with a contact sensitizer reduces the aberrant expression of MHC-I and MHC-II molecules on the lower hair follicle epithelium. From these data it can be concluded that treatment with a contact sensitizer restores the immune privilege of the lower hair follicle epithelium 26.
Although it is known that the immunomodulatory effects of NB-UVB are very important in the treatment of many skin diseases, it is also known that UVB is absorbed in the upper dermis, whereas UVA penetrates to the deeper dermis. Therefore, NB-UVB cannot penetrate to the lymphocytic infiltration around the hair follicle 12. These observations could explain the better response of our patients to KUVA therapy compared with NB-UVB therapy.
Lassus et al. 17 reported good prognostic criteria for PUVA in AA, including late onset of AA, that is after 20 years of age and less than a 5-year duration of alopecia. In contrast, in the present study, we did not find any significant correlation between clinical responses to both therapeutic modalities and the age of onset of AA or the duration of disease. This is in accordance with the results of Healy and Rogers 27.
All clinical forms of AA in our study, except AU, responded to KUVA therapy; this is in agreement with the results of Tritrungtasna et al. 14. In addition, the two patients with AU who were treated with NB-UVB therapy, in our study, did not respond to therapy.
Lassus et al. 17 mentioned localized AA as being among the good prognostic criteria for PUVA effectiveness. In the present study, although the frequency of clinical response to KUVA therapy was higher among patients with localized AA with SALT score less than 50% it did not reach statistical significance. This may be attributed to the small sample size in our study.
It is important to mention that both treatment modalities were well tolerated with no phototoxic reactions in any of our patients. This is in accordance with the results of Tritrungtasna et al. 14 and Bolduc et al. 10.
Unlike PUVA therapy, which had a very high relapse rate in the treatment of AA 27, Tritrungtasna et al. 14 reported that KUVA therapy had no relapse rate; they reported no recurrence in their patients after a follow-up period of 2 months. This is in contrast to our study in which we found a relapse rate of 50% in patients treated with KUVA therapy. This higher relapse rate may be attributed to the longer duration of follow-up (3 months) and the small sample size in our study. In addition, no relapse was detected in the two responders to NB-UVB after 3 months of termination of therapy, which is in contrast to the results of Krook 22, who reported a high relapse rate of AA after UVB therapy. The small number of responders to NB-UVB in the present study makes commenting on the relapse rate after termination of therapy difficult.
On the basis of our results, we can conclude that KUVA therapy is better than NB-UVB therapy in the treatment of AA resistant to other treatment modalities. All clinical forms of AA, except AU, are likely to respond to KUVA therapy, whereas only patients with patchy AA are likely to respond to NB-UVB therapy. Both treatment modalities are safe with no phototoxic reactions.
The clinical response to both therapeutic modalities seems uninfluenced by the age at onset of AA and duration of the disease.
Further controlled large-scale studies on KUVA and NB-UVB therapy in the treatment of AA should be carried out with longer follow-up durations.
Conflicts of interest
There are no conflicts of interest.
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