Remission period in psoriasis after multiple cycles of narrowband ultraviolet B phototherapy

Authors

  • Hyeong Ho Ryu,

    1. Department of Dermatology, Seoul National University Hospital, Seoul, Korea
    Search for more papers by this author
  • Yun Seon Choe,

    1. Department of Dermatology, Seoul National University Hospital, Seoul, Korea
    Search for more papers by this author
  • Seongmoon Jo,

    1. Department of Dermatology, Seoul National University Hospital, Seoul, Korea
    Search for more papers by this author
  • Jai Il Youn,

    Corresponding author
    1. Department of Dermatology, National Medical Center, Seoul, Korea
    • Correspondence: Jai Il Youn, M.D., Department of Dermatology, National Medical Center, 18-79 Euljiro 6-Ga, Jung-Gu, Seoul 100-799, Korea. Email: jaiil@snu.ac.kr and Seong Jin Jo, M.D., Department of Dermatology, Seoul National University Hospital, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, Korea. Email: sj.jo@snu.ac.kr

    Search for more papers by this author
  • Seong Jin Jo

    Corresponding author
    1. Department of Dermatology, Seoul National University Hospital, Seoul, Korea
    • Correspondence: Jai Il Youn, M.D., Department of Dermatology, National Medical Center, 18-79 Euljiro 6-Ga, Jung-Gu, Seoul 100-799, Korea. Email: jaiil@snu.ac.kr and Seong Jin Jo, M.D., Department of Dermatology, Seoul National University Hospital, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, Korea. Email: sj.jo@snu.ac.kr

    Search for more papers by this author

Abstract

The aim of this study was to investigate the duration of remission periods in psoriasis after narrowband ultraviolet B (NB-UVB) phototherapy, especially during multiple cycles of treatment. We analyzed 63 patients (101 cases) demonstrating marked improvement after NB-UVB phototherapy. The remission period was defined as the duration of time from the end of phototherapy until treatment using either phototherapy or systemic treatments was required again. It was found that an age of 60 years or older, history of systemic therapy within 6 months and three or more phototherapy cycles were significantly associated with shorter remission periods. Furthermore, multivariate analysis confirmed that three or more phototherapy cycles (odds ratio [OR], 4.0; 95% confidence interval [CI], 1.73–9.33; = 0.001) and a history of systemic therapy (OR, 2.2; 95% CI, 1.27–3.95; = 0.005) were independently associated with the shorter remission period. In conclusion, when planning NB-UVB phototherapy for psoriatic patients who have undergone multiple phototherapy cycles, clinicians should consider the possibility of shorter remission periods.

Introduction

Narrowband ultraviolet B (NB-UVB) phototherapy is a first-line treatment option for severe psoriasis because of its efficacy and safety. Indeed, the efficacy of NB-UVB phototherapy is almost equivalent to that of psoralen plus ultraviolet A (PUVA) therapy without the inconvenience and toxicity of psoralen.[1] Thus far, no studies have established an association between NB-UVB phototherapy and increased risk of skin cancer, whereas PUVA therapy has been reported to increase the risk of skin cancer.[2] However, NB-UVB phototherapy causes skin tanning, which may affect the efficacy of treatment.[3, 4] One report has suggested that NB-UVB phototherapy should be administrated at least 10 months after the preceding treatment to allow for recovery from tanning.[4]

Given that psoriasis is chronic and was incurable until now, it is very common to repeat phototherapy or systemic therapy to manage re-exacerbated psoriasis. Therefore, considering the remission period after successful treatment with NB-UVB is clinically important.[5] However, there are only a few studies about the duration of remission periods after NB-UVB phototherapy, despite its efficacy being investigated in many studies.[6] According to these studies, patients who have undergone systemic therapy or phototherapy have significantly shorter remission periods after NB-UVB phototherapy than those of patients who have not received systemic therapy or phototherapy previously,[7] but treatment frequency (twice vs three-times weekly)[8] and maintenance therapy do not significantly influence remission periods.[5] However, the association between multiple cycles of phototherapy and its remission period has not been established from long-term follow-up studies of psoriatic patients. Thus, we investigated the associations between different clinical factors, including the number of phototherapy cycles, and duration of remission periods in psoriasis.

Methods

Subjects

The medical records of psoriatic patients were retrospectively reviewed to gather cases treated with NB-UVB phototherapy at the outpatient clinic of Seoul National University Hospital, Seoul, Korea, from August 1999 until December 2011. Only patients who achieved a 90% improvement in their Psoriasis Area and Severity Index (PASI) score or a grade IV, indicating an improvement of over 95% according to the grading system proposed by the PUVA Cooperative Group of the USA,[9] were included. We excluded subjects who discontinued phototherapy because of adverse events and had received concomitant systemic therapy. This study was approved by the institutional review board of Seoul National University Hospital (no. H-1307-058-504).

NB-UVB phototherapy schedule

In the conventional NB-UVB phototherapeutic schedule used in our department for psoriasis, TL-01 lamps in a UV 7001K cabin (Waldmann, Villingen-Schwenningen, Germany) are utilized. Ultraviolet irradiation was performed two or three times a week. The initial dose was determined by the minimal erythema dose or the luminance value (L*) using a Minolta Spectrophotometer CM-20021 (Konica Minolta, Tokyo, Japan).[10] Doses were increased incrementally, usually by 10% or 20% of the previous dose, until the psoriatic plaque cleared. These doses were modified according to individual responses and side-effects, which included erythema, irritation and itching. If needed, ointments containing vitamin D3 or steroids, or both vitamin D3 and steroids, were applied topically. A “cycle” of phototherapy was defined as one complete session of phototherapy that continued until psoriatic clearance was achieved.

Assessments and statistical analyses

We defined psoriatic re-exacerbation as the time when patients took treatment with any systemic therapy or phototherapy or reached 50% or more of the initial PASI score or coverage of 10% or more of the body surface area. The following clinical and demographic characteristics were obtained from the patients' medical records: age, sex, duration of disease, type of psoriasis, initial PASI scores, history of systemic therapy or phototherapy, frequency of irradiation, total irradiation dose, the number of cycles of phototherapy and the interval between each phototherapy cycle.

We conducted univariate and multivariate analyses to investigate the associations between different clinical characteristics and psoriatic remission periods. Univariate analysis was performed using correlation analyses (Pearson's product–moment correlation coefficient and Spearman's rank correlation coefficient) for numerical variables and Kaplan–Meier survival analysis was performed for categorical variables. For the correlation analyses, we excluded patients who were not followed up for more than 12 months if there were no re-exacerbations, and we set the follow-up period as the remission period. For the Kaplan–Meier survival analysis, the groups were compared using the log–rank test, the Breslow generalized Wilcoxon test, and the Tarone–Ware test. The groups' baseline characteristics were compared using the χ2-test for categorical variables and Student's t-test or the Mann–Whitney U-test for numerical variables, depending on the sample size. When evaluating the influence of sex, type of psoriasis and history of systemic therapy on the remission period, we only used data from the first treatment cycle that had been performed at our hospital for each patient to avoid duplicating data from the same patients. Multivariate analysis was performed to account for the factors associated with remission periods at the < 0.1 significance level in the univariate analysis. These factors were further analyzed using Cox proportional hazard regression models to select factors independently associated with psoriatic re-exacerbation at the 5% significance level. Analysis was performed using the IBM SPSS Statistics 21.0 software package (IBM, New York, NY, USA).

Results

Study sample

A total of 101 cases (63 patients) were evaluated in this study. The baseline demographic and clinical characteristics of the cases are shown in Table 1. The median age was 44.6 years (range, 18–88), and the mean duration of psoriasis was 14.9 years (range, 0–36). Nummular psoriasis was the most common type of psoriasis, and most of the patients' skin types were classified as Fitzpatrick skin phototypes IV and V. The mean cumulative NB-UVB dose was 39 346.4 mJ/cm2 (range, 2470–97 010). The mean follow-up duration was 9.5 months (range, 0–74), and psoriatic re-exacerbation occurred in 66 cases after 9.2 months (range, 1–35). In the 11 patients with previous systemic therapy within 6 months, two patients had been treated with oral retinoids, five patients with cyclosporin and the other four patients with unknown systemic agents in other hospitals.

Table 1. Demographic and clinical characteristics of the cases included in this study
  1. a

    The numbers in parentheses refer to number of patients. SD, standard deviation; PASI, Psoriasis Area and Severity Index.

Age, years, mean ± SD44.6 ± 14.4
Sex, n, men/women56/45 (37/26)a
Duration of psoriasis, years, mean ± SD14.9 ± 9.0
Type of psoriasis, n, guttate/nummular/large plaque11/48/30 (5/27/22)a
Fitzpatrick's skin phototype, n, IV/V28/12 (16/7)a
Initial PASI score, mean ± SD17.0 ± 5.3
No. of treatments, mean ± SD23.5 ± 8.7
Cumulative dose, mJ/cm2, mean ± SD39 346.4 ± 21 422.9

Univariate analysis of the clinical factors associated with remission periods

As shown in Figure 1, cases aged 60 years or older (= 12) had longer remission periods than those who were less than 60 years old (= 89) (= 0.04). In addition, the older cases had fewer treatments (mean, 21.1 vs 23.9, respectively) and lower cumulative doses (mean, 27 726.4 vs 40 886.4 mJ/cm2, respectively), but these differences were not statistically significant. When cases aged less than 60 years were grouped according to age in 10-year intervals, there were no significant differences among the groups in relation to the remission period.

Figure 1.

Kaplan–Meier survival analysis showed that cases aged over 60 years (= 12) had longer psoriatic remission periods than younger cases (= 89) (= 0.04).

In addition, survival analysis about the remission period after the first phototherapy of each patient showed that patients who had received systemic therapy within 6 months of undergoing phototherapy (= 11) had shorter remission periods than those who had not received systemic therapy (= 52) (< 0.001) (Fig. 2). There were no significant differences between these groups in relation to the number of treatments and the total irradiation dose.

Figure 2.

Kaplan–Meier survival analysis showed that patients with a history of systemic therapy (= 11) had significantly shorter remission periods than those who had not received systemic therapy (= 52) (< 0.001).

Spearman's rank correlation analysis demonstrated that the number of phototherapy cycles administrated was significantly associated with the remission period (= 0.006). In addition, fewer than three cycles of phototherapy were associated with a significantly longer remission period compared with three or more phototherapy cycles (= 0.007) (Fig. 3). There were no significant differences between these groups in relation to initial PASI scores, number of treatments received and the total irradiation dose.

Figure 3.

Cases with a history of three or more phototherapy cycles (= 37) had significantly shorter remission periods than those with a history of less than three phototherapy cycles (= 64) (= 0.007).

Other clinical factors including sex, disease duration, type of psoriasis, initial PASI scores, frequency of irradiation per week and the total irradiation dose were not significantly associated with the remission period (Table 2).

Table 2. Statistical analysis of the relationships between clinical variables and the psoriatic remission period
Clinical variablesStatistical methodP-value
  1. a

    The analyses were performed with data from the first treatment cycle for each patient to avoid data duplication. PASI, Psoriasis Area and Severity Index.

Sex (= 63)aKaplan–Meier survival analysis0.346
Duration of disease (= 73)Correlation analysis0.586
Type of psoriasis (= 54)aKaplan–Meier survival analysis
Guttate vs nummular0.638
Guttate vs large plaque0.938
Nummular vs large plaque0.101
Initial PASI scoreCorrelation analysis (= 24)0.104
 Kaplan–Meier survival analysis (= 28); PASI ≥15 vs <150.364
Frequency of irradiation (= 101)Kaplan–Meier survival analysis: twice a week vs three times a week0.778
Total irradiation dose (= 71)Correlation analysis0.490

Multivariate analysis of clinical factors associated with remission periods

Multivariate analysis using Cox proportional hazard regression models showed that history of systemic therapy within 6 months (odds ratio [OR], 4.0; 95% confidence interval [CI], 1.73–9.33; = 0.001) and three or more cycles of phototherapy (OR, 2.2; 95% CI, 1.27–3.95; = 0.005) were independently associated with short remission period.

Subgroup analysis of the interval between each phototherapy cycle

To determine whether the interval between each phototherapy cycle was related to the remission period, we conducted subgroup analysis of the cases who had received multiple cycles of NB-UVB phototherapy (= 36). Linear regression analysis showed that the interval between each phototherapy cycle was significantly associated with the remission period (β ± standard error, 0.374 ± 0.130; = 0.007) (Fig. 4a). Survival analysis showed that a treatment interval of more than 9 months was significantly associated with a greater remission period compared with a treatment interval of less than 9 months when the Breslow generalized Wilcoxon (= 0.010) and Tarone–Ware (= 0.018) tests were used. This relationship had a borderline significance when the log–rank test was used (= 0.061) (Fig. 4b). There were no significant differences between these two groups in relation to age, the number of phototherapy cycles undergone, administration of previous systemic therapy and the total irradiation dose.

Figure 4.

Association between the interval between each cycle of phototherapy and the remission period. (a) Linear regression analysis showed that the interval between each phototherapy cycle was associated with the remission period (β ± standard error, 0.374 ± 0.130; = 0.007). (b) A treatment interval longer than 9 months was significantly associated with a longer remission period compared with a treatment interval that was shorter than 9 months based on the Breslow generalized Wilcoxon test (= 0.010) and Tarone–Ware test (= 0.018); however, a borderline significance was attained using the log–rank test (= 0.061).

Discussion

Narrowband ultraviolet B phototherapy has frequently been used to treat psoriasis, either as monotherapy or in combination with topical ointments, oral retinoids and/or biologic agents.[6] Its therapeutic effect is achieved by a combination of alterations in the cell cycle, cytokine changes and suppression of pathologically relevant T cells.[1] NB-UVB phototherapy generally induces a relatively long remission period that may be partly due to the apoptosis of T cells.[11] An imbalance between T-helper (Th)17 cells and regulatory T cells (Treg) is thought to contribute to the pathogenesis of psoriasis.[12] NB-UVB phototherapy reduces levels of Th17 cells and increases Treg cell levels.[11, 13]

In this study, univariate analyses showed that psoriatic cases aged 60 years or more had significantly longer remission periods than cases younger than 60 years. There were no significant differences between the groups in relation to the number of treatments and the cumulative dose, suggesting that this finding was not biased by individual phototherapy schedules. The longer remission periods observed in the older cases may be a consequence of the decreased proliferative capacity of lymphocytes due to aging[14] and/or the greater permeation of the skin by ultraviolet B light because of age-related skin atrophy. However, multivariate analysis showed that age was not significantly associated with the remission period of psoriasis. To confirm the influence of age on the remission period of psoriasis, studies involving larger patient populations are required.

Both univariate and multivariate analyses demonstrated that a history of systemic therapy within 6 months was significantly associated with the shorter remission period. This finding is consistent with that of a previous study in which the authors suggested that psoriatic activity is higher in patients who had received previous systemic therapy than in those who had not.[7] In the present study, we investigated whether systemic therapy received within 6 months as opposed to systemic therapy received over a lifetime had an influence on psoriatic remission, because we believe that high disease activity is indicated by rapid re-exacerbations or psoriasis that is recalcitrant to recent systemic therapy.

In this study, the initial PASI score was not associated with the remission period on either correlation or survival analyses, which probably reflects the severity of psoriasis rather than the disease activity. Our finding suggests that the activity and severity of psoriasis are distinct aspects of the disease and that disease activity is more important in the remission period.

Three or more phototherapy cycles were also associated with a shorter remission period. This may mean that patients who need more courses are those who have psoriasis that is harder to treat and more likely to relapse with high disease activity. However, we should consider another possibility that multiple cycles of phototherapy shortened the remission because multiple phototherapy cycles were not significantly related to the higher initial PASI scores, number of treatments received, and the total irradiation dose to achieve 90% improvement in PASI score or almost clear state of psoriasis. Although one cycle of phototherapy may not have a marked impact on reducing the remission period, there are possible causative factors that have a cumulative effect. First, phototherapy-induced skin tanning can prevent the transmission of light and may result in the patient receiving the equivalent of a low-dose treatment schedule. Second, the repertoire of T cells may change to become refractory to phototherapy. Recently, Furuhashi et al.[11] reported that Th17 cell levels were higher in poor-responder patients than in good-responder patients after NB-UVB phototherapy and Th17 cell levels in patients who received repeated phototherapy tended to be higher than those in patients who had never received phototherapy in their preliminary study.[11] To clearly analyze whether repeated phototherapy is the cause of short remission period, the development of clinical markers indicating psoriatic activity, not PASI – which is a severity marker – is needed. There were some previous reports about biomarkers such as high-sensitivity C-reactive protein,[15, 16] interleukin (IL)-22,[17] IL-17,[12] IL-20,[18] endocan,[19] vascular endothelial growth factor, transforming growth factor-β1 and nitric oxide[20] which were associated with disease severity and decreased by treatment. Further well-designed studies for evaluating the association between these biomarkers and remission period will be needed.

Clinicians should consider skin tanning caused by NB-UVB phototherapy when planning the re-administration of phototherapy to patients who experience psoriatic re-exacerbations. Skin tanning recovers over time. In a previous study, it took 10 months for L*, which describes relative lightness, to reach a level that did not differ significantly from the initial value obtained before phototherapy, and 8 months for the individual typology angle, which provides a means to quantitatively classify an individual's skin colour,[4] to approximate the initial angle. Therefore, in this study we assumed that an adequate duration between phototherapy cycles may reinstate the remission period associated with multiple cycles of phototherapy. We performed subgroup analysis to evaluate the association between the interval between each phototherapy cycle and the remission period, and using the Breslow generalized Wilcoxon and Tarone–Ware tests we found that an interval of more than 9 months was associated with a longer remission period. As these two tests give greater weight to the initial period, unlike the log–rank test, we can infer that a short interval between each phototherapy cycle is associated with early psoriatic re-exacerbation. However, this finding should be interpreted with caution because a short interval between each phototherapy cycle may imply high disease activity, resulting in a short remission period.

This study has some limitations owing to its retrospective nature. First, the phototherapy regimen was not controlled, but because there was no significant difference between the groups analyzed, we consider that this limitation did not have a marked effect on the study. Second, we failed to extract clinical information such as obesity, presence of metabolic syndrome and body surface area from medical records, which may be associated with the disease severity. Third, our study sample size was relatively small. Though our study results were statistically significant, further research with large sample size will be needed to form a solid conclusion.

In conclusion, we found that a history of systemic therapy and multiple cycles of phototherapy were significantly associated with short remission periods after NB-UVB phototherapy. When multiple cycles of phototherapy had been administrated, a short interval between each cycle was associated with short remission periods. We suggest that when clinicians treat psoriatic patients with NB-UVB phototherapy, they should consider these clinical factors to achieve longer remission periods.

Conflict of interest

The authors have no conflicts of interest to declare.

Ancillary