|Year : 2014 | Volume
| Issue : 2 | Page : 81-85
Advancements in photodermatology - 2013: Part II. Clinical research
Medhat El-Mofty, Wedad Z Mostafa, Rehab A Hegazy
Department of Dermatology, Faculty of Medicine, Cairo University, Cairo, Egypt
|Date of Submission||09-Nov-2014|
|Date of Acceptance||09-Dec-2014|
|Date of Web Publication||29-Jan-2015|
Wedad Z Mostafa
MD, 10 Gameyet, El Nesr St., Dokki 12311, Cairo
Source of Support: None, Conflict of Interest: None
Photochemotherapy is considered a key tool for dermatologists in treating numerous, diverse conditions. Accordingly, there is a continuous effort to evaluate the well-settled indications, seek new ones for these lines of treatment, singly or in combination, aiming at better results and fewer side effects. The limitations and risks that photochemotherapy bears and the proper management plans are other fields of interest. In this article we will discuss some of the important clinical research studies in the domain of photochemotherapy published during the past year in an attempt to emphasize the up-to-date recommendations, widen our therapeutic scope, and expand our forthcoming research plans as dermatologists and researchers.
Keywords: 2013, clinical research, photochemotherapy
|How to cite this article:|
El-Mofty M, Mostafa WZ, Hegazy RA. Advancements in photodermatology - 2013: Part II. Clinical research. Egypt J Dermatol Venerol 2014;34:81-5
|How to cite this URL:|
El-Mofty M, Mostafa WZ, Hegazy RA. Advancements in photodermatology - 2013: Part II. Clinical research. Egypt J Dermatol Venerol [serial online] 2014 [cited 2017 Dec 18];34:81-5. Available from: http://www.ejdv.eg.net/text.asp?2014/34/2/81/150251
| Introduction|| |
Several studies were carried out to achieve a deeper insight into the clinical indications that could best benefit from this tool, as well as the best combinations, the possible risks, and the management of those risks. Herein, we will discuss the most important clinical studies conducted in the field of photodermatology in the past year.
| New evaluations of old indications|| |
Broad-band ultraviolet A, a promising tool
Both narrow-band ultraviolet B (NB-UVB) and PUVA are regarded as corner-stones in vitiligo therapy ,. In relatively high (15 J/cm 2 ) and repeated (three times weekly) doses, UVA has the capacity to induce both immediate pigment darkening and delayed tanning, mechanisms of action that proved to be very beneficial for vitiligo patients in a study conducted at the Phototherapy Unit, Kasr Al-Ainy . Subsequently, the efficacy of broad-band ultraviolet A (BB-UVA) (15 J/cm 2 ) was compared with NB-UVB in 40 patients with NSV . After 48 sessions, BB-UVA showed a significantly better final percentage of clinical improvement compared with NB-UVB. Furthermore, in a study on 45 NSV patients, BB-UVA (15 J/cm 2 ) yielded comparable results to PUVA, proposing its comparable value when oral psoralens are contraindicated . The main drawback of BB-UVA was the significantly longer session duration. In addition, the long-term safety of BB-UVA needs recognition through vertical studies. Nonetheless, these studies re-enforced the proposed potential of adding BB-UVA to the armamentarium of therapies available for treating vitiligo.
Narrow-band ultraviolet B combination treatments
The utilization of NB-UVB in combination with other treatments for vitiligo has always been a point of interest, with controversial results on their worthiness. In this sense, a clinical trial  was conducted on 45 NSV patients with an aim to compare the efficacy of NB-UVB alone versus in combination with topical calcipotriol or with both topical calcipotriol and β-methasone. All therapeutic lines yielded a 47-63% improvement in repigmentation. There was no significant difference between either combination groups; however, both were significantly better than NB-UVB alone. Furthermore, Wong and Lin  - based on double-blind studies - concluded that pimecrolimus 1% cream combined with NB-UVB is superior to NB-UVB alone, especially for facial lesions. Hence, NB-UVB combination therapies seem to be a more logical decision in the treatment of NSV.
The use of a fire needle has been recently introduced as a possible combination option with NB-UVB in the treatment of NSV . The fire needle is a local needling technique used within Japanese acupuncture and is believed to keep pathogens away. In a clinical trial intending to evaluate this newly proposed combination treatment, 93 cases of NSV received NB-UVB, with 45 of them receiving adjuvant fire needle. The fire needle was applied around the vitiliginous skin, with NB-UVB therapy irradiating the local area. Clinical efficacy was evaluated after a treatment period of 12 weeks. The significant superiority of this combination was evident through the significantly higher degree of repigmentation documented in this group. We believe that this work could be added to the collection of studies pointing to the possible advantageous influence of some traumas in the treatment of vitiligo [9-11], a concept worthy of further documentation and clarification.
Phototherapy and segmental vitiligo
Segmental vitiligo (SV) is usually characterized by a unilateral-dermatomal distribution, early onset, and rapid progression, followed by stabilization. The response to phototherapy in patients with SV is generally believed to be limited. The treatment response in 39 cases of SV was evaluated on the basis of disease duration . Patients with shorter disease duration (≤5 months) yielded significantly better repigmentation responses compared with patients with longer disease duration (>5 months). The results of this study emphasize the need to start treatment as early as possible in patients with SV, as time is certainly of essence.
A systematic review
Ultraviolet (UV)-based therapies, including NB-UVB, broad-band ultraviolet B (BB-UVB), and PUVA, are well-known treatment options for moderate-to-severe plaque psoriasis. However, evidence-based reviews on their efficacy, short-term safety, and tolerability are limited. In an attempt to fill this void, systematic review and meta-analysis  were performed on 41 randomized control studies and 2416 psoriatic patients. It concluded that, as a monotherapy, PUVA was more effective than NB-UVB, and NB-UVB was more effective than BB-UVB and bath PUVA in the treatment of adults with moderate-to-severe plaque-type psoriasis, based on clearance as an endpoint. On the basis of PASI-75, the results were similar except for BB-UVB, which showed a high mean PASI-75 that was similar to PUVA. The short-term adverse effects were mild, as shown by the low rate of withdrawal due to adverse effects. The results of this systematic review serve as a further proof to the 'survival' of PUVA in the face of NB-UVB therapy, through superior efficacy and comparable short-term side effects.
A comparative study
NB-UVB and calcipotriol are both well-documented lines of therapy in psoriasis, whether separately or in combination. In a comparative study, Takahashi et al.  divided 40 psoriasis patients randomly into four groups. Groups I, II, III, and IV received topical calcipotriol twice daily, NB-UVB monotherapy (with placebo) more than twice weekly, combined topical calcipotriol twice daily with NB-UVB once weekly, or combined topical calcipotriol twice daily with NB-UVB more than twice weekly, respectively. After 12 weeks of therapy, group IV patients showed results superior to the other treatment regimens, yielding the most marked and rapid reduction in PASI. This study confirms the importance of combination therapies in psoriasis, which result in better efficacy, shorter treatment duration, and thus fewer side effects. Another important point highlighted by this study is that providing NB-UVB in combination does not justify reducing the frequency of its sessions, as sessions are needed at least twice/week to achieve good results.
Broad-band ultraviolet A, a promising tool (again)
The standard treatment of early-stage mycosis fungoides (MF) is PUVA and NB-UVB . UVA1 phototherapy was found to induce marked clinical and histopathological improvement of skin lesions in patients with stages IA and IB . UVA1 represents 80.1% of the BB-UVA spectrum ,, with similar mechanisms of action ,,. Aiming to evaluate the efficacy of BB-UVA in the treatment of early-stage MF, 30 patients with early-stage MF were divided into two equal groups, receiving either BB-UVA at 20 J/cm 2 or PUVA three times/week for 40 sessions . Patients were further followed up for an average duration of 36 months. On the basis of clinical and histopathological evaluations, as well as, immunohistochemical measurement of CD4+ cells and Bcl-2, BB-UVA proved to be significantly superior over PUVA in inducing a more rapid clearance rate, requiring shorter time to achieve complete clearance, and in reaching both a longer disease-free interval and a lower relapse rate. Avoiding the usage of psoralens with UVA permits administration of higher doses of UV, thus allowing more frequent apoptosis to occur - an accepted explanation to this impressive response.
This latter study introduced BB-UVA (20 J/cm 2 ) as a good alternative in the treatment of early-stage MF when contraindications to psoralen exist, when deeper penetration is needed, or when UVA1 is not available, especially in patients with dark-skin phototypes who are tolerable to such dose without phototoxicity . Potential long-term side-effects of BB-UVA need verification to evaluate risk/benefit ratio in a potentially malignant disease such as MF.
Long-term follow-up after narrow-band ultraviolet B therapy
Data concerning relapse rates and relapse-free intervals of early-stage MF patients after achieving complete response (CR) with NB-UVB phototherapy is far from clear. In response to this requirement a retrospective study  evaluated data belonging to early-stage MF patients treated with NB-UVB phototherapy between May 2000 and July 2010, and followed up until May 2012 in a single institution, for the occurrence of relapse and the time to relapse. Of 31 patients, who were followed up for a mean of 56.5 ± 30.2 months, relapse was observed in 11 (35.5%) patients within a mean of 28.8 ± 18.2 months, whereas 20 (64.5%) patients remained relapse-free for a mean of 54.2 ± 28.8 months. Such data highlights the ability of NB-UVB phototherapy to induce low relapse rates and long relapse-free intervals for early-stage MF, an effect that is of great value in such a persistent disease.
Hypopigmented mycosis fungoides and phototherapy
Hypopigmented MF is an uncommon variant of MF and, to date, there are only a few reports on UV-based treatment for this condition. To analyze the efficacy of PUVA photochemotherapy and NB-UVB phototherapy for hypopigmented MF, Wongpraparut and Setabutra  retrospectively studied data of nine patients who had received either modality. The clinical response, total number of treatments, cumulative UV doses, disease-free interval, and adverse effects were recorded. Eight patients had stage IA and one patient had stage IB. Six patients had received NB-UVB and three patients had received PUVA. Three (50%) patients in the NB-UVB group and three (100%) patients in the PUVA group had CR. The total UV dose required to get maximal clinical response was 27.1-59.6 J/cm 2 in the NB-UVB group and 244-669.1 J/cm 2 in the PUVA group. Of six patients who attained CR, four (66.7%) developed recurrence, and the disease-free interval ranged from 2 months to 6 years. Although both PUVA and NB-UVB are effective for hypopigmented MF, PUVA appeared superior and both showed common disease relapse.
Whether parapsoriasis represents an early stage of cutaneous T-cell lymphoma (CTCL) is still a subject of controversy. To test the relation between both disease entities, as well as the efficacy of phototherapy in the treatment of parapsoriasis, Duarte et al.  studied 62 patients diagnosed with parapsoriasis (45 with large type and 17 with small type). They received phototherapy PUVA (45 patients) or NB-UVB (17 patients) for 30 sessions regardless their type. Following treatment, disease evolution was closely observed for 1-8 years. In all patients the complete cure rate approached 80% and improvement of the lesions was evident in nearly 17% of the patients. During the follow-up period, the two (3%) poor responders, both with large plaques, developed CTCL. In an answer to the two proposed questions, this study emphasizes the fact that parapsoriasis has no general tendency to progress to CTCL and that phototherapy is an excellent treatment choice for parapsoriasis, with high cure rates, regardless of the modality used. It indicates the possible value of closely following up poor responders to phototherapy, who apparently are at a greater risk of developing CTCL compared with the good responders.
Pityriasis lichenoides (PL) is a self-limiting papulosquamous disease that may persist for years and is associated with a high relapse rate. Studies comparing the efficacy of NB-UVB phototherapy and other therapies in its treatment are quite few. In this retrospective study  on 70 patients with PL, the efficacy of NB-UVB as a monotherapy was compared with systemic steroids and/or systemic antibiotics and with both NB-UVB plus systemic medication. All three modalities were successful in terms of efficacy (>90% improvement in skin lesions) and the time needed to achieve this response (average 8 weeks) without statistically significant difference, with better results surprisingly documented in the NB-UVB monotherapy group. This study sheds light on the high efficacy of NB-UVB in the treatment of PL, and further abolishes the need to offer systemic therapy either alone or in combination. Still, the long-term efficacy of such a modality is in need of further clarification.
Oral lichen planus
The potential malignant transformation of oral lichen planus makes it a compulsory therapeutic challenge. Kvaal et al.  examined the clinical behavior and response to topical methyl-5-aminolevulinate photodynamic therapy in the treatment of this disease in 14 patients. A radiant exposure of 75 J/cm 2 of red light in the region 600-660 nm was delivered at irradiances of 100-130 mW/cm 2 using a light-emitting diode light source. The high efficacy of this therapeutic line was evident from a single session in which all patients demonstrated significant improvement. What is even more noteworthy is that none of the patients showed evidence of relapse in the 4-year follow-up period. This lasting improvement after a single treatment places methyl-5-aminolevulinate-photodynamic therapy among the 'treatment of choice' list for oral lichen planus.
Both PUVA and NB-UVB are widely accepted therapeutic modalities in cases of chronic urticaria but with no published comparative studies between the two modalities. In an answer to this requirement, Khafagy et al.  compared the efficacy of PUVA with NB-UVB in the treatment of 24 cases of chronic urticaria based on the urticaria Total Severity Score and side effects. A significant decrease in urticaria Total Severity Score in both the NB-UVB-treated and PUVA-treated groups was documented, with no significant difference between the two groups. Gastrointestinal upset was reported at a significantly higher percentage in the PUVA-treated group. This study confirmed the efficacy of both NB-UVB and PUVA in the treatment of chronic urticaria, and for the first time demonstrates that both modalities show comparable efficacy with minimal reversible side effects.
Moderate-to-severe eczema in children
This study was performed aiming for prospective evaluation of the efficacy of NB-UVB in children with eczema using objective scores . The study comprised 55 children aged 3-16 years, resistant to prescribed topical medications, and for whom NB-UVB was indicated; of them, 29 children underwent the treatment and 26 chose not to. Both groups were evaluated using the Six Area Six Sign Atopic Dermatitis score, percentage of surface area involvement, and quality-of-life score at baseline, 12 weeks (end of treatment) and 3 and 6 months after NB-UVB. All assessed scores yielded significantly better results in the NB-UVB receiving group at all times of assessment. This study comes as a further documentation to the efficacy of NB-UVB and its positive influence on the improvement on the quality of life in children with moderate-to-severe eczema with a maintained effect for 6 months after treatment.
| Potential risks and their management|| |
Exposure to UV radiation is known to lead to suppression of many adaptive immune responses, both to antigens encountered within a short period of the irradiation (primary) and to antigens previously encountered (memory). However, the pathways involved are complex and not completely elucidated. The complexity stems from the variable players involved in this process.
This brief overview  clearly highlighted the main proceedings of that complex event. The resulting immunosuppression could be viewed as a double-edged weapon that should be carefully balanced. With the appropriate protocol in the suitable patient, NB-UVB would represent a beneficial therapeutic tool to combat inflammatory and autoimmune diseases. One should always be cautious not to cross the line and thereby avoid the postulated risks of skin cancer, photosensitivity diseases, as well as decreased resistance to some infectious diseases and immune response to some vaccines.
Melanoma and nonmelanoma skin cancer in patients with vitiligo
Recent genetic studies suggest a lower susceptibility to melanoma in patients with vitiligo; however, lifetime melanoma prevalence in patients with vitiligo is an overlooked issue. Furthermore, nonmelanoma skin cancer (NMSC) prevalence in vitiligo patients has been investigated, but only in small studies and with contradictory results. Another intriguing point would be the influence of phototherapy received by vitiligo patients on such prevalence. In an answer to those inquiries Teulings et al.  conducted a retrospective, comparative cohort survey that included 1307 NSV patients aged 50 years or older. Their results revealed a threefold lower probability of developing melanoma and NMSC in patients with vitiligo. Taking matters a bit further, subgroup analyses of patients treated with NB-UVB and PUVA did not show dose-related trends of increased age-adjusted lifetime prevalence of melanoma or NMSC. This study emphasizes the fact that vitiligo patients are in a rather 'safe zone' with respect to melanoma and NMSC development and that their receiving phototherapy - regardless the modality - does not push them away from this zone.
Ultraviolet-induced risk in melanocytic nevi
Melanocytic nevi have been observed to undergo morphological changes following exposure to NB-UVB. Lin et al.  comprehensively analyzed 440 melanocytic nevi in a cohort of 51 patients receiving NB-UVB. Four dermatologists examined each nevus for specific clinical and dermoscopic features, as well as determined the size of each nevus by planimetry, immediately before NB-UVB treatment, after 10 exposures, after 30 exposures or at the end of treatment if earlier, and 3 months after discontinuing treatment. The most common global dermoscopic patterns in the 440 nevi examined were reticular (50%) and globular (32%). Following NB-UVB exposure, blurring or merging of lines was observed in 45% of reticular nevi. An increase in color intensity and in the number of dots or globules was observed in 63% of globular nevi. Furthermore, around half of the nevi underwent a change in size either by increase (46%) or, 'surprisingly', by decrease (54%). Adding to this, nevi that enlarged tended to revert to pretreatment size 3 months after discontinuation of phototherapy. This study further documents the undeniable changes that melanocytic nevi express when exposed to NB-UVB, but points to the rather benign nature of such changes.
Ultraviolet-induced photoaging and the effect of mild heat
The search for protective measures against postulated risks of phototherapy is endless. The protective effect of heat on the UVB-induced photoaging has been explored. The exact temperature appears as a key factor; mild heat pretreatment (42°C) was found protective against UVB-driven skin aging, whereas severe heat pretreatment (≥43°C) induces per se skin aging. This protective effect is attributed to the ability of mild heat exposure to stimulate upregulation of heat shock protein 70 chaperones, which in turn inhibit the activities of matrix-degenerating enzymes, thereby avoiding wrinkle formation. This newly identified heat-mediated process of adaptation to UVB radiation exposure opens new opportunities to slow extrinsic skin aging, and urges the trial of other low-dose stressors .
| Conclusion|| |
The rapidly expanding nature of the field of phototherapy is never-ending, and this review offers but a glimpse on this mounting territory. It attempts to cover most of the important studies concerned with photodermatology published during the past year, throwing light on the latest inquiries, investigations, mechanisms, conclusions, and recommendations. Such knowledge would indeed improve the service provided to patients and direct steps in upcoming research plans in the domain of phototherapy.
| Acknowledgements|| |
Conflicts of interest
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