Phototherapy and vitiligo
Mechanisms of action
Narrowband ultraviolet B (NB-UV) is accepted as the cornerstone therapy for vitiligo. Despite the apparent clinical efficacy, the underlying mechanisms of how NB-UVB improves vitiligo have not been clearly elucidated 1, driving several researchers to try to unravel this issue.
T-regulatory cells (Tregs) are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and abrogate autoimmune disease 2. Autoimmunity being one of the most accepted hypotheses to explain the pathogenesis of nonsegmental vitiligo (NSV) 3 has triggered an array of studies documenting the possible roles played by Tregs in such a disease 4–10.
Taking a step further, during the past year, two studies 11,12 addressed the possible influence of NB-UVB on the expression of Tregs in vitiligo patients. One 11 evaluated its effect on the circulating CD4(+) CD25(high) FoxP3(+) Tregs, whereas the other 12 determined the tissue expression of FoxP3 as a marker for Tregs in lesional and perilesional skin. Compilation of the results of both of these studies indicates that, before therapy, the percentage of circulating Tregs in vitiligo patients was significantly higher than in controls 11, whereas their tissue expression was significantly lower 12. A reversal of those findings, with significant decrease in the circulating Tregs expression 11 and increased tissue expression 12, followed NB-UVB. Accordingly, it may be hypothesized that a defect in the function of Tregs is one of the keys to the immunological disruption seen in NSV. In addition, NB-UVB may be assumed to exert its therapeutic effect at least partially through augmentation of Tregs, improving their function as well as their homing capacity, representing a novel pathway through which NB-UVB induces clinical improvement in NSV. Furthermore, the restoration of the balance between Tregs and T-helper cells (17) in the perilesional skin 12 offers further explanation for the stabilizing effect exerted by NB-UVB on vitiligo 13–15.
The oxidant–antioxidant imbalance is regarded as another possible culprit in the complex story of vitiligo 16–18. In a trial 19 to elucidate the effect of NB-UVB phototherapy on oxidative stress markers, erythrocyte superoxide dismutase activity, erythrocyte malondialdehyde, and erythrocyte glutathione peroxidase activity levels were assessed in 24 patients with vitiligo at baseline, and after NB-UVB phototherapy. NB-UVB phototherapy was associated with a significant reduction in malondialdehyde levels and a significant increase in glutathione peroxidase levels. This reversal of the oxidant–antioxidant imbalance in vitiligo patients might yet represent another mechanism by which NB-UVB improves this disease.
Comparison of phototherapy with other modalities
Potent topical corticosteroids
NB-UVB phototherapy is considered a first-line treatment for extensive vitiligo because of the relatively good efficacy and excellent tolerance 20. In contrast, topical steroids are indicated for the therapy of limited areas of vitiligo 21. Clobetasol propionate is the most powerful of these drugs and is available in a variety of forms. Both cream and ointment formulations have been reported to be effective in the therapy of vitiligo 22–24. A topical formulation of 0.05% clobetasol propionate foam (CPF) (VersaFoam; Connetics, Palo Alto, California, USA) has been available since 2006, with no highlight on its possible use in vitiligo despite its documented success in the treatment of other dermatoses as psoriasis 25, chronic hand dermatitis 26, atopic dermatitis 27, alopecia areata 28, and delayed pressure urticaria 29. In response to this gap, Stinco et al. 30 compared the efficacy and tolerability of CPF with that of NB-UVB phototherapy in a retrospective study on 60 NSV patients (localized, generalized, and acrofacial). The efficacy of CPF was significantly higher compared with NB-UVB in all anatomical sites. However, a higher incidence of side effects was reported in the CPF group (13.33 vs. 0%) in the form of mild transient erythema with itching, which disappeared shortly in three patients, as well as diffuse edema in one patient that necessitated discontinuation of therapy. These findings suggest that CPF may be promising in vitiligo. However, further larger-scale studies conducted over longer durations are needed to confirm these preliminary observations.
Topical calcineurin inhibitors
Topical calcineurin inhibitors are among the armamentarium of therapeutics used in the treatment of vitiligo 31. Tacrolimus and pimecrolimus were introduced as topical immunomodulators for vitiligo and proved as equally effective as clobetasol 32–35. Recently, it was shown that tacrolimus augments the pigmentation and migration of human melanocytes 36. The twice daily application of tacrolimus 0.1% ointment proved overall to be comparably effective to NB-UVB, as measured by mean time to initial repigmentation and mean percent repigmentation, to once 37 and twice weekly NB-UVB exposures 38. Both studies proposed the consideration of tacrolimus ointment 0.1% as an alternative to NB-UVB therapy in treating vitiligo.
Despite numerous therapeutic options, many patients with vitiligo remain in the refractory state 39. This has led to the evolution of various surgical modalities to treat stable lesions, including autologous noncultured epidermal cell suspensions and cultured melanocyte suspensions 40. The importance of combining any surgical procedure with NB-UVB is an undisputed fact that was recently rehighlighted in a report on 437 stable vitiligo patients 41. After undergoing cultured autologous melanocyte transplantation, patients were randomly assigned to four different groups, receiving either NB-UVB treatment before transplantation, NB-UVB treatment after transplantation, NB-UVB treatment before and after transplantation, or receiving no NB-UVB. The group that received NB-UVB before and after transplantation responded best, with achievement of 90% repigmentation in 81.3% of patients. This study emphasizes the beneficial influence of combining NB-UVB with the surgical procedure in cases of stable vitiligo, particularly when administered both before and after transplantation.
Newer combination regimens
Afamelanotide, a synthetic analog of the naturally occurring α-melanocyte-stimulating hormone, has been shown to induce skin pigmentation through melanogenesis and to reduce ultraviolet-induced damage 42. Afamelanotide is currently being tested in an implant delivery formulation and is clinically trialed for a series of conditions affecting the skin, including erythropoietic protoporphyria, polymorphous light eruption, solar urticaria, phototoxicity associated with systemic photodynamic therapy, actinic keratosis, and lately vitiligo 43.
In a randomized multicenter trial 44, 28 patients with generalized NSV received a combination therapy, where after 1 month of NB-UVB phototherapy 16 mg of afamelanotide was administered subcutaneously monthly for 4 months while NB-UVB phototherapy continued. Patients showed a clinically significant superior and faster repigmentation response compared with 27 patients who received NB-UVB monotherapy for a similar duration. Response was more noticeable in patients with skin phototypes IV to VI, on face and arms in particular. It thus appears that this combination regimen with α-melanocyte-stimulating hormone could potentiate the NB-UVB, hence improving therapeutic results and minimizing exposure and doses.
Novel topical cream
Although the treatment efficacy of NB-UVB artificial light sources is well documented, the long time and cost commitment of therapy continue to form a barrier to treatment adherence. Natural sunlight is without doubt an ideal source of accessible UVB radiation, especially in sunny climates; however, exposure to natural sunlight generally results in erythema before the accumulation of sufficient amounts of therapeutic wavelengths of UVB 45.
In 2013, McCoy et al. 45 introduced a novel topical cream that when combined with natural sunlight permits the therapeutic wavelength of 311 nm to pass and prevents other wavelengths. This cream contains two molecules that were found best for delivering NB-UVB from natural sunlight: α-glucosyl hesperidin, a glycosylated derivative of a natural plant flavonoid, and diethylamino hydroxybenzoyl hexyl benzoate. Goren et al.46,47 decided to utilize their discovery and as a continuation of their promising in-vitro work performed two pilot studies to determine the efficacy and safety of this cream in the treatment of both vitiligo 46 and psoriasis 47. Promising results were described in vitiligo after an average of 11 weeks of treatment in which all patients responded to therapy: 56% showing greater than 50% repigmentation versus 10% showing 20% repigmentation on placebo. Similarly, in psoriasis after an average of 38 sessions, all patients responded to treatment showing complete clearance in 43% and a minimum of 50% clearance in the rest. In contrast, none of the patients in the placebo arm experienced more than 20% lesion clearance. These preliminary results offer a hope for finding a safe, effective, and convenient alternative to artificial light phototherapy that could lead to better patient compliance.
Psoriasis between phototherapy and biological therapy
Biologics, FDA approved for the treatment of psoriasis since 2002, act through targeting the immune system at specific steps in the pathogenesis of psoriasis, altering the natural history of the disease 48. Although biologics have been proven to have great efficacy, a trouble-free magic bullet has not been discovered as hoped for. Financial burden limits their use by many patients, and they are not approved for the treatment of psoriasis in children. In addition, their use is associated with various risks, including immunosuppression and malignancy, both lymphoproliferative and cutaneous 49.
Moreover, loss of response with time has been reported 50. Different strategies have been designed to avoid those risks, such as shortening the treatment interval or combining with other modalities 51. Combination therapy provides the advantage of synergic efficacy while achieving a reduction in the required dose, thus diminishing the side effects of individual therapeutic agents, and has become, in some practices, almost routine in the management of moderate and severe psoriasis 52,53. Several clinical studies have shown that the combination with NB-UVB light improves the efficacy of tumor necrosis factor-α inhibitors 54–60 as well as ustekinumab 61 for moderate to severe psoriasis, wherein NB-UVB was used during the induction phase with biologic treatment, resulting in a faster and higher response rate compared with the use of biologic agents alone.
To evaluate NB-UVB/biologics combination, a retrospective chart review conducted recently by Belinchón et al. 51 included 17 patients with moderate to severe psoriasis who had ceased to respond to biological treatment monotherapy [etanercept (n=8), adalimumab (n=4), ustekinumab (n=3), efalizumab (n=1), and infliximab (n=1)]. Sixteen patients showed more than 75% improvement in their Psoriasis Area Severity Index (PASI) scores, proving the efficacy of this combination therapy.
However, UVB phototherapy is potentially carcinogenic (although this has not yet been shown for 311-nm UVB in humans), and there are safety concerns, particularly in its combination with biological agents 61, where experimental data showed that the combination of antitumor necrosis factor-α drugs with NB-UVB alters cyclin D1, p53, and survivin, thus increasing the risk for photocarcinogenesis 62.
In an attempt to evaluate this risk, a study was conducted by Inzinger et al. 63. Twenty-nine chronic plaque psoriasis patients who had been treated by combining 311-nm UVB with at least one biological agent [etanercept (n=5), adalimumab (n=6), golimumab (n=2), ustekinumab (n=9), and alefacept (n=14)] were screened for non melanoma skin cancer and melanoma and followed up for 234 weeks after the first combination treatment. None of the study cases developed non melanoma skin cancer or melanoma, proving the safety of the combination of NB-UVB with biologics at least on short-term to intermediate-term basis. However, further studies are still needed to assess the long-term risks of such a combination.
Finally, although biologic therapy has proven highly efficacious, phototherapy remains the keystone for psoriasis treatment, providing an excellent benefit-versus-risk profile. Moreover, phototherapy (NB-UVB) provides an excellent therapeutic option for combination with biologics whether during the induction phase or to restore initial response after repeated therapy.
Mycosis fungoides: phototherapy and safety concerns
Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma. It occurs most commonly during mid to late adulthood, with a median age at diagnosis of 55–60 years. However, it is estimated that 0.5–5% of cases develop during childhood 64.
Phototherapy has been used as first-line treatment for the management of MF in both children and adults. NB-UVB therapy has been used mainly for early patch-stage MF, whereas psoralen plus ultraviolet A has been used in plaque-stage disease and patch-stage MF refractory to NB-UVB as well as folliculotropic MF 65. The need for prolonged and repeated courses of treatment has raised long-term safety concerns.
Bath psoralen plus ultraviolet A in mycosis fungoides
Pavlotsky et al. 66 treated 26 adult patients diagnosed with folliculotropic MF (n=14) and NB-UVB-refractory early-stage MF (n=12) with 0.2 mg/l 8-methoxypsoralen bath three times weekly followed by UVA irradiation at 0.3 J/cm2 with fixed increments every second session. After an average of 33 weeks (cumulative radiation dose of 158 J/cm2), a complete clinical response was achieved in 62% of patients. The high cost and need for special bathing units, however, limit the use of bath psoralen plus ultraviolet A. Also, the long duration of treatment and need for sun avoidance are inconvenient for many patients 67.
Phototherapy in childhood mycosis fungoides
Only a few studies have tackled MF in the pediatric population 64,68–70. A 5-year retrospective study evaluated the efficacy and safety of NB-UVB phototherapy in the management of MF in children 64. The study evaluated nine children with MF who had undergone 2–3 weekly NB-UVB phototherapy sessions for a mean duration of 9 months with an average cumulative dose of 1300–2497 mJ/cm2. NB-UVB was found to be safe and effective in inducing clinical remission in all study patients, with the time to complete response ranging from a few months to up to 2 years. However, long-lasting remission was seen in only one-third of patients, as two-thirds relapsed within 2 years. An interesting finding was that hypopigmented lesions were seen in all study patients. An earlier report highlighted the frequent occurrence of hypopigmented MF in children compared with adults 71.
Handheld phototherapy devices
Home phototherapy provides an excellent alternative for patients who have difficulty travelling to phototherapy centers 72. Despite several studies demonstrating the feasibility of home phototherapy 73,74 and encouraged use in the medical press, it is still not generally available. The main reason behind the limited use of home phototherapy machines is the concern regarding side effects and efficacy 75. Concerns were raised mainly in the USA and Canada, where patients buy their own units, treatment is poorly supervised, side effects poorly monitored, and use is often for longer term maintenance rather than for short course therapy until remission is achieved 75,76.
In 2014, Cameron et al. 77 analyzed the home phototherapy database of the already available service between 1998 and 2011 at the Photobiology Unit of Ninewells Hospital, UK, to assess the efficacy, safety, and cost-effectiveness of hospital-supervised home phototherapy. A total of 298 courses of home NB-UVB phototherapy were undertaken by 212 patients between 1998 and 2011. The main diagnoses managed were psoriasis (72%), atopic dermatitis (8%), and desensitization of photodermatoses (7%). For psoriasis, 74.5% achieved clearance or minimal residual activity in a median of 30 exposures. The total cost to society (hospital and patient costs) is around £410 per course, compared with an estimated £550 for outpatient therapy for this group of patients. Treatment was well tolerated, erythema rates were similar to those of outpatient therapy, there were no complaints, and the vast majority would choose home over outpatient phototherapy if required in the future.
The reason for the success of home phototherapy according to this review 77 is hospital supervision, wherein patients undergo training when attending minimal erythema dose testing (to determine a safe starting dose), usually for 1 h, and when the minimal erythema dose is read 24 h later. Moreover, the session of therapy is supervised in the department, supported by a manual developed by the lead home phototherapy nurse. In conclusion, supervised home phototherapy by adequately trained patients who can manage the treatment unit is a safe and cost-effective strategy.
Handheld phototherapy in treatment of acne keloidalis
Acne keloidalis nuchae (AKN) is a chronic scarring folliculitis with fibrotic papules on the occipital scalp with high prevalence in men of African descent 78. Only a few interventional studies have addressed the use of nonsurgical, minimally invasive treatments 79. Ultraviolet irradiation induces the production of several members of the matrix metalloproteinase (MMP) family, which degrade collagen fibrils and other components of the dermal extracellular matrix 80,81. In addition, MMPs regulate various inflammatory, repair, and immune processes. MMPs are also key players in activating transforming growth factor β, a ubiquitously expressed cytokine with multiple regulatory properties depending on cell type, growth conditions, and context-specific cofactors 82. On the basis of the AKN fibrotic pathogenesis and the efficacy of NB-UVB to reverse it through induction of MMPS and collagen degradation, a randomized, split-scalp comparative study was conducted on 11 patients with AKN 83. One randomly selected side of the scalp was treated with targeted UVB up to three times weekly for 8 weeks, and then both sides were treated for 8 additional weeks. Most treated AKN lesions responded to UVB therapy, and new lesions ceased to occur during the treatment period. There was a significant difference between treated and untreated areas with respect to the mean lesion count reduction (P=0.009), patient self-assessment, and analysis of MMP1, MMP9, transforming growth factor β1, and collagen 1 (COL1A1) mRNA expression by quantitative reverse-transcription PCR. This pilot study provides strong evidence for the efficacy and safety of UVB therapy in the treatment of AKN.
Phototherapy beyond the skin level
The effects of phototherapy go beyond the skin level and thus could offer a beneficial effect in nondermatological diseases. The systemic influence of phototherapy is a proven fact in numerous studies 84,85 and has been recently utilized in the treatment of multiple sclerosis (MS) 86.
Breuer et al.86 studied the effects of UVB light in a murine model of autoimmunity, and 11 patients with relapsing-remitting MS were treated with NB-UVB phototherapy. The patients showed clinical improvement as well as an increase in induced Tregs and tolerogenic dendritic cells, accompanied by the downregulation of the T-cell effector cytokine interleukin 21. The treatment further induced elevated serum levels of vitamin D. This improvement was explained by the communication between local cutaneous and systemic immunity through the induction of Tregs and Tregs-induced tolerogenic dendritic cells locally in the skin-draining lymph nodes in response to UVB exposure. This links the cutaneous immune response to central nervous system immunity by migration to the sites of inflammation (blood, spleen, central nervous system) where they attenuate the inflammatory response and ameliorate disease symptoms. These data may have implications for expanding the disease territory in which phototherapy could offer a helping hand in modern times, while providing new hope for patients with MS and similar systemic neurological immunopathies.
Despite all therapeutic advances we believe that ‘What’s new in phototherapy?’ is a question that will never lose its value. It still bears endless answers that a large sector of dermatologists will remain eager to keep updated with. In the current review the most important and intriguing studies were elaborated in a trial to keep up with the latest and most updated work, offer a deeper understanding of this imperative tool, and open new doors for more advanced research.
Conflicts of interest
There are no conflicts of interest.
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