Patient reported outcomes for intensified versus conventional NB-UVB treatment in non-segmental vitiligo

Abstract

Introduction: Treatment of non-segmental vitiligo (NSV) remains a challenge. Efficacy of NB-UVB treatment may increase with more frequent use or in combination with topical agents. Currently, data on the most effective treatment regimen lacking. Our objective is to retrospectively compare NB-UVB treatment regimens for non-segmental vitiligo.

Methods: Patients with NSV treated with NB-UVB therapy were included in two time periods. Group I received NB-UVB therapy twice a week (conventional treatment) and group II received NB-UVB thrice a week, combined with topical agents (intensified treatment). Patients completed a questionnaire regarding the degree and onset of repigmentation, satisfaction and side effects.

Results: Repigmentation scores did not differ significantly between the two groups. Onset of repigmentation in the first three months seemed higher in group II, but this difference was not significant (23.4% vs 51.1%; p = .11). In both groups the majority of the patients were moderately to very satisfied (group I: 70.2% group II: 73.3%). The occurrence of adverse effects was comparable.

Conclusions: This study indicates that conventional and intensified treatment for NSV seem to be comparable. The intensified treatment might be more effective to speed up the onset of repigmentation, but larger prospective studies are needed to objectify these findings.

Keywords:

• Non segmental vitiligo
• treatment
• NB-UVB

Introduction

Non-segmental vitiligo (NSV) is an acquired chronic pigment disorder of the skin characterized by the development of patchy leukoderma, with a significant negative effect on the quality of life (1–3). NSV is the most common depigmenting disorder affecting approximately 1% of the world’s population, regardless of gender, ethnicity or skin type (4). Current treatments include topical agents, phototherapy and surgical techniques which aim to improve melanocyte proliferation and stimulate repigmentation (5). Topical therapy with corticosteroids or calcineurin inhibitors are suggested as first-line treatment (6). The use of narrow band ultraviolet B (NB-UVB) phototherapy was first reported in 1997 by Westerhof et al. (7) and is now considered to be a growing modality for the treatment of generalized NSV (5). NB-UVB is superior to psoralen and UVA (PUVA, another commonly used phototherapy regimen in vitiligo) due to its increased efficacy and decreased adverse effects (8,9).

Currently, no consensus exists as to what the optimal treatment regimen and duration is of NB-UVB phototherapy, and practice varies widely (10). At the Academic Medical Center (AMC), conventional treatment for NSV was NB-UVB alone twice a week, but this has changed in an intensified schedule with NB-UVB thrice a week in combination with topical treatment with fluticasone propionate and/or tacrolimus. This change was implemented in 2011 due to recent studies showing that the combination of topical therapy and NB-UVB is superior to monotherapy (11,12). However, data on the most effective treatment frequency are lacking. Until now, the NB-UVB treatment regimens have never been compared directly. For the use of NB-UVB expert recommendations have been developed based on current literature by the Vitiligo Working Group Phototherapy Committee (13). However, little evidence is available to guide clinicians on what is the most effective duration, dosage and treatment frequency of NB-UVB. Two studies have investigated the difference in effectiveness between twice and thrice weekly treatment regimens for vitiligo with the 308-nm excimer laser (14,15). Both studies demonstrate that the final repigmentation does not depend on the treatment frequency but on the total number of treatments. However, the onset of repigmentation does occur faster with the three times weekly treatment. This could be the same for NB-UVB phototherapy but studies investigating this hypothesis are lacking.

For future improvement of vitiligo therapy it is important to assess, compare and evaluate the current treatment regimens, in order to determine what is most effective and satisfactory for the patient. Therefore, the aim of this study is to explore whether a combination of NB-UVB three times weekly and topical agents is superior to NB-UVB alone twice a week for the treatment of non-segmental vitiligo from patients’ perspectives.

Materials and methods

Patients

This retrospective cohort study was performed at the Netherlands Institute for Pigment Disorders in Amsterdam. Inclusion criteria were: (i) diagnosis of non-segmental vitiligo; (ii) age 16 or older; (iii) received total body NB-UVB therapy for at least six months.

Patients were included in two different time periods: Group I finished their NB-UVB therapy between March 2008 and January 2009. Group II finished their therapy between February 2017 and October 2017. Questionnaires were sent to the patients within four months after the end of the NB-UVB therapy. In between these time periods the standard of treatment had changed (see treatment). Inclusion criteria were patients aged 16 years or older, diagnosed with NSV who received total body NB-UVB therapy at home prescribed for one year.

Patients were sent the questionnaire with a consent form and a return envelope. If a patient did not respond, he or she was reminded by phone with a maximum of three follow-up calls. In case a patient was not reachable by phone a second questionnaire was sent by post. This study was not subject to the WMO (Medical Research Involving Human Subjects Act) and approval was granted by the Medical Ethical Committee of the AMC.

Treatment

In both groups NB-UVB treatment was given at home. The equipment comprised of semi-circular Waldmann UV-100 units with TL-01 tubes. These tubes contain ultraviolet B lamps that irradiate light with a wavelength of 311 nanometer. Standardized cumulative doses were calculated by using the intensity measurements together with the treatment charts of patients. Nursing staff cared for guidance and explanation of the NB-UVB equipment and treatment.

In group I irradiation took place twice a week on nonconsecutive days. The patients were not advised to use an additional topical treatment except emollients. In group II irradiation was given thrice a week on nonconsecutive days with topical therapy on the non-irradiation days, consisting of a calcineurin inhibitor (tacrolimus or pimecrolimus) for lesions on the face and skinfolds and a corticosteroid such as fluticasone propionate 0.005% for lesions on the rest of the body. Patients were advised to increase the intensity by 50 mJ/cm2 if no suberythema of the skin occurred directly after the NB-UVB therapy. When suberythema occurred, an equal dose was recommended for the next irradiation and when painful erythema or blisters were observed patients were instructed to omit the next treatment.

Questionnaire

A questionnaire comprising 21 questions was constructed (Supplementary Appendix I). Questions included patient characteristics, disease duration, The Vitiligo Disease Activity (VIDA) score for disease activity and previous treatments. Patients were requested to note the repigmentation percentage per treatment area (face, neck, trunk, arms, hands, legs and feet) and to state the onset of repigmentation. Additionally, patients were asked to rank their level of satisfaction regarding the result of the therapy and the appearance of the repigmentation. Seven questions were included about the NB-UVB regimen such as average times of irradiation per week and total amount of months of the treatment. Additionally, patients were asked whether they had used topical therapy and if so, which topical agent was used and the average application of the cream per week. Finally, questions were asked about adverse effects; temporary occurrence of suberythema, painful erythema and a burnt skin.

Statistical analysis

All statistical analyses were conducted using SPSS software version 24.0 for Windows (Armonk, NY, USA). Mean scores between both groups were compared using the t-test and Mann-Whitney-U test for normally and not-normally distributed numerical variables, respectively.

For categorical variables Chi-square tests were performed to analyze differences between the groups. The Spearman’s rank correlation test was used to define the association between the onset of repigmentation and patient satisfaction within the groups.

Statistical tests were two-sided and the statistical level of significance was set at p < .05.

Results

Patient and treatment characteristics

A total of 109 eligible patients with non-segmental vitiligo aged 16 years or older were sent the questionnaire. The response rate was 47 (87%) in group I and 45 (82%) in group II. The patient characteristics are presented in Table 1. The two groups were comparable regarding age, duration of disease, previous treatments and skin type. The Vitiligo Disease Activity (VIDA) scores showed no significant differences in disease activity between the two groups (p = .46).

Table 1. Patient characteristics.

	Group I (conventional), N = 47	Group II (intensified), N = 45
Male:female ratio	1:1.8	1:1.1
Mean age ± SD (min–max)	43 ± 13 (17–68)	46 ± 14 (21–74)
Disease duration >5 years	66%	56%
Skin type
I	2%	4%
II	55%	64%
III	34%	11%
IV	4%	7%
V	4%	13%
VI	0%	0%

SD: standard deviation.

Treatment characteristics and results are shown in Table 2. Patients in group II received significantly more irradiation per week. Of this group 96% had used additional topical agents during the irradiation period: 88% applied tacrolimus 0.1% for the face with a mean number of 3.3 times per week and 79% applied fluticasone propionate 0.005% with a mean application of 3.2 times per week. Other creams such as Pimecrolimus and Betamethasone were used by 9% of the patients.

Table 2. Characteristics and results of treatment.

	Group I (conventional)	Group II (intensified)	p-value
Mean number of treatments per week	2.3	3.0	<.001*
Time investment per week in minutes, median [IQR]	20 [10–40]	25 [12–40]	.72
Missed – more than 10 treatments	13%	27%	.38
Suberythema – more than 20 times	40%	42%	.27
Painful erythema occurrence – more than 10 times	8.5%	4.4%	.79
Blistering	0%	4.4%	.14

* significant.

The majority of patients in both groups were treated more than nine months with the NB-UVB therapy (group I 68%, group II 83%). The median cumulative doses in group I and II were 62.3 (N = 47) and 63.8 J/cm2 (N = 22), respectively. In the intensified group half of the cumulative doses (23 patients) were unknown due to incomplete treatment charts of the patients.

Repigmentation and satisfaction

The median repigmentation within the two groups differed widely for different body sites. The median repigmentation for the face and neck were reported slightly higher in group II, this difference was not significant. In both groups, patients reported that acral areas tended to repigment less than the face and neck (Table 3). The onset of repigmentation in the first three months seems higher in group II, but this difference is not significant (Group I 23.4%, group II 51.1%; p = .11) (Figure 1). The start of repigmentation in both groups was predominantly reported in the first six months (66% of the group I and 80% group II).

Figure 1. The onset of repigmentation per patient group. No significant differences were found between groups (Chi square test, p=.11).

Table 3. Median repigmentation (%) at different body sites at the end of therapy.

	Group 1 (conventional )	N	Group II (intensified)	N	p-value
	Median [IQR]		Median [IQR]
Face	60 [6–80]	28	75 [11–90]	40	0.20
Neck	40 [30–70]	19	50 [9–80]	25	0.79
Trunk	30 [10–55]	30	20 [6–50]	33	0.50
Arms	40 [10–60]	29	25 [6–60]	31	0.49
Hands	10 [0–30]	31	3 [0–30]	32	0.37
Legs	35 [6–58]	24	40 [6–70]	33	0.78
Feet	0 [0–15]	17	0 [0–5]	25	0.60

IQR: interquartile range.

Additionally, a significant correlation between the onset of repigmentation and satisfaction of the result was found in group II (intensified); Spearman’s rho .44, p = .003. In group I (conventional) this correlation was not significant (Spearman’s rho .28; p = .064). The majority of the patients were moderately to very satisfied in both groups (conventional group 70.2% versus intensified group 73.3%, p = .91) (Figure 2).

Figure 2. Satisfaction with result after one year NB-UVB therapy per patient group. No significant differences were found between groups (Chi square test, p=.91).

Furthermore, most of the patients would recommend their treatment to others (98% of the conventional group, 89% of the intensified group; p = .08).

Discussion

This questionnaire study examined patient reported outcomes regarding repigmentation and satisfaction in non-segmental vitiligo patients after completing NB-UVB therapy. According to this retrospective study, the intensified treatment regimen with NB-UVB thrice a week in combination with topical agents does not seem to be superior to the conventional treatment regimen with NB-UVB twice a week.

Our NB-UVB protocol changed from twice to thrice a week (in combination with topical therapy), however no reports are available demonstrating the superiority of one above the other. Previous studies indicate that repigmentation is dependent on the total number of light treatments (14,15). Earlier onset of repigmentation has been seen in the thrice weekly regimen, which seems to be comparable to our study. Similar results have been observed in a study comparing twice and thrice weekly NB-UVB therapy for psoriatic patients (16). Furthermore, systematic review studies comparing combination therapy (NB-UVB and topical calcineurin inhibitors) with monotherapy (NB-UBV) showed improved repigmentation for the combination therapy, especially in the face and neck (17,18). However, we cannot confirm this in our study.

To our knowledge, our retrospective study is the first to compare different treatment regimens with each other from patients’ perspectives. A strength of our study was that it concerns real life data from clinical practice. Another strength is that it had equal and comparable treatment groups regarding baseline patient and treatment characteristics, which was essential to make proper comparisons between the two different treatment regimens. In addition, the surveys were only sent to patients that had recently completed their NB-UVB therapy, which kept the recall bias as limited as possible.

However, there are some limitations to this study that need to be addressed. Firstly the study was performed in two different time periods with a 10 year interval, patients expectations might have changed over time. Since the prognosis and treatment regimens for vitiligo have not changed much in this period we expect this difference to be small. Furthermore this study was based on daily practice, additional therapy (such as topical agents and skin transplantation) during NB-UVB therapy were allowed in the conventional group. This could have had an influence on the outcomes and makes a proper comparison between our treatment regimens more difficult. Moreover, not all cumulative doses were known of the patients in the intensified group due to incomplete treatment charts. The observation that the final repigmentation per body site was comparable for both groups may be due to the similar cumulative doses in both groups. However this cannot be objectified due to the fact that not all cumulative doses could be determined. Another important limitation is the lack of validated outcome measures. However, it is remarkable that the percentage of repigmentation in the various body locations is compatible with the expected response pattern in both groups. Finally, disease extent and comorbidity were not assessed, although these factors might influence the patients’ perspective on the therapeutic outcomes.

The design of our study was constructed in such a way that two and three times weekly NB-UVB therapy could not directly be compared with each other; we also added the topical treatment to our standard of care. A direct comparison between twice weekly and thrice weekly NB-UVB in vitiligo patients is still needed to determine what the optimal frequency is. It is possible that the additional topical treatment is responsible for the earlier repigmentation in the intensified group. Thus, prospective studies are required, since it is difficult to critically investigate these regimens in retrospective study designs due to the possible variations in dosimetry, irradiation time and other outcome measures. A twice-weekly regimen might be more convenient regarding time and effort for patients. However, this could be accompanied by psychological distress experienced by patients due to slow responses, leading to reduced therapy compliance (13).

In conclusion, this study shows that the twice-weekly and thrice-weekly regimen in combination with topical agents seem to be comparable regarding patient reported repigmentation, satisfaction and occurrence of short term adverse effects. Though, patients seem to notice an earlier onset of repigmentation in the intensified group, this difference is not significant. Finally, the start of repigmentation in the intensified group significantly correlates with the satisfaction after completing the NB-UVB therapy. The intensified treatment might be more effective to speed up the onset of repigmentation, but costs and burden should be taken into account. Larger prospective studies are needed to objectify these findings.

Acknowledgements

We would like to express our gratitude to the volunteering patients who participated in this study.

Disclosure statement

No potential conflict of interest was reported by the authors.