Phototherapy and Photopheresis

Old and New Indications

Filipa Osório; Sofia Magina

Disclosures

Expert Rev Dermatol. 2011;6(6):613-623. 

In This Article

Phototherapy

Phototherapy is the use of UV radiation in the treatment of skin disease.[1] Radiation within the UV spectrum can be divided by wavelength into UVC (200–280 nm), UVB (280–320 nm) and UVA (320–400 nm). Owing to the filtering effect of the earth's atmosphere, almost all UVC radiation and approximately 90% of the UVB is absorbed. Consequently, UVA makes up approximately 95% of the UV radiation that reaches the earth. With its longer wavelength, it can penetrate deep into the dermis, while UVB is absorbed in the epidermis. It is mainly UVB that burns the skin because it possesses much more energy than UVA (energy is inversely proportional to wavelength).[1]

Types of phototherapy include broadband-UVB (BB-UVB, 290–320 nm, peaks at 313 nm), narrowband-UVB (NB-UVB, 311–313 nm), UVA1 (340–400 nm, peaks at 365 nm), and combination therapy of psoralen plus UVA (PUVA photochemotherapy, 320–400 nm, peaks at 352 nm).[1,2] Available psoralens include 8-methoxypsoralen (8-MOP; only form available in the USA), 5-methoxypsoralen (5-MOP; primarily used in Europe) and 4,5,8-trimethoxypsoralen.[2] The psoralen can be administered orally (5-MOP or 8-MOP) or topically, either in the form of ointment, cream or lotion, either as bath-PUVA (8-MOP, 5-MOP or 4,5,8-trimethoxypsoralen).[2,3] These treatment modalities are generally administered in a light booth or by hand and/or foot units.[2]

Recently, the xenon chloride gas excimer offers a means for delivering larger fluences of 308 nm UVB selectively to the cutaneous lesions, with a decreased carcinogenic potential. Two systems have been developed: laser technology (known as excimer laser) and a new nonlaser technology (known as excimer light). The advantages of excimer light over the laser system are low operating costs and the fact that a large area can be treated quickly.[4]

Photodynamic therapy and low-level light therapy are out of the scope of this review.

Mechanisms of Action

The following mechanisms have been proposed to explain UV's efficacy in the treatment of skin diseases:

  • Apoptosis of pathogenically relevant cells, including T-cell apoptosis, in the treatment of psoriasis, mycosis fungoids and atopic dermatitis,[5,6] and mast-cell apoptosis, for pruritic skin disorders;[7]

  • Apoptosis of keratinocytes;[8]

  • Enhancement of melanocyte proliferation, for vitiligo;[2]

  • Decreased release of histamine from both basophils and mast cells, for histaminic disorders such as urticaria pigmentosa;[2]

  • Inhibition of ICAM-1 upregulation by keratinocytes in inflammatory diseases (which acts as counter-receptor for lymphocyte function-associated antigen-1 on the surface of leukocytes);[9]

  • Downregulation of Th17 signaling pathway and decreased expression of IL-10 by keratinocytes, with a subsequent reduction of IFN-γ signaling and an anti-inflammatory effect.[10,11] Phototherapy has also been found to decrease the expression of IFN-γ-inducing cytokines IL-12, IL-18 and IL-23;[12]

  • Increased expression of immunosuppressive cis-urocanic acid levels in the skin, resulting in suppression of cellular immune response and inhibition of antigen-presenting function of Langerhans cells.[2,13]

In psoralen plus UVA (PUVA) photochemotherapy, psoralens photoconjugate to DNA with subsequent suppression of DNA synthesis and cell proliferation.[14] Also, reactive oxygen species production (derived from psoralens reacting with molecular oxygen) causes mitochondrial dysfunction and leads to apoptosis of Langerhans cells, keratinocytes and lymphocytes.[2]

Dosing & Administration

Before starting UVB phototherapy, the minimal erythema dose (MED) should ideally be determined (erythema 24 h after exposure).[2,15] It is advised that the first treatment of NB-UVB equals 0.7 MED and that dose increments are made according to postirradiation erythema.[2,15] It is also possible to utilize Fitzpatrick skin type-dependent starting doses with subsequent fixed increments,[15] and this is the approach we use in our center (Hospital de São João, Porto, Portugal). In the clearing phase, treatments are given 2–5-times weekly.[15]

UVA-1 is further classified as low dose (20 mJ/cm2), medium dose (50–60 mJ/cm2) and high dose (120–130 J/cm2). Theoretically, full dose can be used as a starting dose because UVA1 does not induce erythema. However, to avoid any idiosyncratic reaction, it has been recommended to start at 20 mJ/cm2, and then increase by 10 J/cm2 per treatment until the full desired medium dose is reached. High-dose UVA-1 is no longer widely used.[2]

In PUVA, the initial dose of UVA can either be determined by minimal phototoxicity dose (MPD; erythema 48–72 h after exposure) or by Fitzpatrick skin type.[2] In the first approach the initial dose should be 0.5–0.7 MPD for oral PUVA and 0.3 MPD for bath PUVA, with subsequent dose increments according to postirradiation erythema.[15] Similar to UVB dosing, UVA doses should be decreased if topical or systemic retinoids are added because they decrease stratum corneum thickness, thereby increasing phototoxicity.[2] In the clearing phase, irradiations are given 2–4-times weekly.[15] For oral PUVA, 0.6–0.8 mg/kg 8-MOP or 1.2–1.8 mg/kg 5-MOP is administered 1–3 h before phototherapy.[3] Bath-PUVA consists of 15–30 min of whole-body immersion in solutions of 0.5–5.0 mg/l 8-MOP or 0.33 mg/l 4,5,8-trimethoxypsoralen.[2,3] Upon exiting the bath, the patient must receive the UVA dose within 30 min.[2]

Safety

Most phototherapy regimens are very low risk for overall patient complications and morbidity.[2]

UVB may cause acute phototoxicity, with erythema and blistering, beginning in the first 4–6 h after exposure and peaking at 12–24 h.[2]

PUVA-induced erythema starts at 24–36 h, peaks at 48–72 h and may last 1 week or more. Avoidance of prolonged sun exposure, wearing UVA-absorbing sunglasses when outdoors, application of broad-spectrum sunscreens, and wearing of photoprotective clothing on the days of PUVA photochemotherapy are necessary measures to prevent significant phototoxicity. 8-MOP has a greater incidence of gastrointestinal side effects than 5-MOP. PUVA's itch is a subacute side effect of this treatment.[2]

Both UVB and PUVA may also lead to tanning (requiring UV-dose increment), photo-onycholysis, melanonychia and friction blisters of treated areas. Photoaging is a long-term side effect, including PUVA lentigines. If proper protective eyewear is not worn, UVB-induced keratitis and PUVA-induced cataracts may also occur.[2] However, the recommendation for regular ophthalmologic evaluation of these patients is still controversial.

With respect to photocarcinogenesis, PUVA is associated with a dose-dependent increased risk of nonmelanoma skin cancers.[16,17] So far, no increase has been documented with NB-UVB,[18] but long-term data are missing. Male genitalia should be shielded during every treatment session as they are particularly sensitive to the development of squamous cell carcinomas (SCCs).[2] Increase in melanoma incidence following UV therapy is controversial.[16,19]

Absolute and relative contraindications to phototherapy and photochemotherapy are shown in Box 1 & Box 2, as described by Sage and Lim.[2] UVB can be used in children as well as in pregnant and breast-feeding women, but long-term safety data are missing. Even though psoralens have never been proved to be teratogenic, they are not generally administered during pregnancy.[2] UVB is considered generally safer than PUVA in patients with skin types I and II, history of melanoma or nonmelanoma skin cancer, past history of x-ray therapy, arsenic exposure, or concomitant use of immunosuppressive agents.[2] Photosensitizing drugs usually react within the UVA spectrum and NB-UVB is thus generally safe in patients taking them.[2] UVB has been shown to be effective and safe in HIV patients,[20] although a small study did show activation of the virus in the skin.[21]

Indications

Psoriasis

UVB Traditional BB-UVB radiation has been used for the treatment of psoriasis for more than 75 years. NB-UVB use was initially popularized in the UK and Europe in the mid-1980s, and became available in the USA approximately one decade later.[22]

NB-UVB is superior to BB-UVB in respect to clearing and remission times,[22] and it currently represents the phototherapeutic modality of choice for the treatment of psoriasis in Europe.[23] However, it is probably not as effective as PUVA, both in terms of clearing efficiency and duration of remission.[15]

Patients with psoriasis who are compliant, motivated and adherent with instructions and follow-up examinations could, under dermatologist supervision, be considered appropriate candidates for home UVB therapy.[22] A recent multicenter, single-blind, randomized clinical trial demonstrated that home NB-UVB is just as effective as outpatient-administered NB-UVB, with superior patient quality of life.[24] We do not have experience with home phototherapy in our center.

In order to improve UVB's efficacy, it can be combined with other treatments, either topical or systemic.

Topical application of calcipotriol (after irradiation) or tazarotene[25] (before irradiation) may increase therapeutic efficacy of phototherapy alone.[26] By contrast, it seems that combining topical steroids adds little benefit to phototherapy.[27] Emmolients can increase UV transmission, increasing efficacy, but thick application of petrolatum and water-in-oil creams as well as salicylic acid and tar act as sunscreens and should be discouraged.[28]

In regard to systemic drugs, retinoids increase efficacy and reduce the carcinogenic potential of UVB phototherapy.[29,30] Retinoids can be maintained after ceasing phototherapy to prevent recurrence. The short time combination of methotrexate with UVB therapy is of potential value because of the synergistic effects of these two therapies.[22] We find this combination particularly useful in patients with psoriatic arthritis in whom the articular disease is successfully managed with low-dose methrotrexate, as phototherapy is not efficacious in treating arthritis. The combination of cyclosporine and UVB has not been studied extensively because of the increased risk of nonmelanoma skin cancer with cyclosporine monotherapy and it should generally be avoided.[22] Combination therapy of UVB with biologics has been reported to have a higher response rate than biologics alone, with a similar safety profile,[22] but further investigation is needed. Potential concerns are increased phototoxicity and photocarcinogenesis.

Although UVB may be adequate for maintenance therapy,[31] it is suggested to consider a rotational therapeutic approach in order to minimize a greater cumulative dose.[32]

The first report on the use of the excimer laser to treat psoriasis goes back to 1997.[33] Advantages include the possibility to treat exclusively the affected skin with higher doses (supra-erythemogenic) and lower number of treatments.[34]

PUVA Compared to oral 8-MOP, oral 5-MOP shows equal clearing rates with a similar number of exposures, but higher cumulative doses, lower incidence of pruritus or severe phototoxic reactions, and no nausea or vomiting.[3]

Compared to oral 8-MOP, bath PUVA shows equal clearing rates with fewer exposures, similar or lower incidence of erythema and pruritus and no systemic intolerance such as nausea or vomiting.[3]

Topical PUVA with psoralen creams, ointment or lotions is now used only for limited plaque psoriasis and for palmo-plantar disease.[3]

With respect to combination therapy, the same considerations are valid as for UVB when it comes to topics. The combination of PUVA with systemic retinoids (RePUVA) is one of the most potent therapeutic regimens for psoriasis.[15] Methotrexate may also be considered for combination therapy, although the long-term risk of cutaneous malignancies, though never proved, should not be forgotten.[15] By contrast, concomitant use of cyclosporine has been recognized to enhance skin carcinogenesis.[35] Further investigation is needed to verify presumptive additive effects of biologics and PUVA.[36]

PUVA can be considered for maintenance therapy but attention should be paid to long-term risks related to total cumulative phototoxic doses.[3]

Pediatric Population: In children, when topical treatment fails, NB-UVB phototherapy in combination with topical agents is generally the recommended treatment option before considering systemic therapy, including retinoids, methotrexate, cyclosporine and biological agents. The long-term risk of NB-UVB light in children is yet to be determined. PUVA can also be considered as a treatment option.[37]

Cutaneous T-cell Lymphoma (Mycosis Fungoides)

PUVA The use of PUVA in cutaneous T-cell lymphoma (CTCL) was first reported in 1976.[38] It is an excellent treatment option for the early stages of the disease (IA–IIA), achieving long-lasting free-disease intervals. It is also capable of reducing tumor burden in later stages (IIB–IVB), where it should be combined with other treatments, such as retinoids, bexarotene, INF-α2a, local x-ray or systemic chemotherapy. Even with aggressive combination therapies, these patients experience multiple recurrences. Although effective in inducing remission in skin-confined disease, the effect of PUVA on the CTCL disease course and overall survival is yet to be determined. Currently there is no treatment option known to arrest progression of later stages.[3,15,39]

After clearing, a maintenance phase is usually recommended, with two sessions per week for 1 month, followed by one session per week for another. Resolution should be confirmed with a biopsy. A follow-up is then performed, either without therapy, with one treatment per month or one treatment every other month. Relapses respond to therapy as well as initial lesions.[3,15]

UVB The first report of UVB phototherapy for CTCL goes back to 1982.[40] NB-UVB can also induce high rates of complete remission in early disease.[39] Evidence is poor, however, regarding the question how NB-UVB compares with other treatments.[39] Studies comparing PUVA and NB-UVB have found them both effective in the treatment of CTCL.[41,42] NB-UVB and BB-UVB therapy have not been compared.

Excimer laser can also be considered a useful tool in the treatment of early-stage mycosis fungoids (MF).[43]

UVA1 UVA1 also appears to be effective,[44] although the experience is limited. It offers advantages over PUVA in terms of side effects.

Pediatric Population: In children, MF is rare and usually limited to early patch-stage disease. Both PUVA and UVB have been used.[37]

Vitiligo

PUVA PUVA has been used for longer than UVB in vitiligo and the available information for this therapy is greater than for UVB.

Patients should be aware that they will require months of treatment (100–200 treatments), with 70% of patients responding after 12–24 months. Responsiveness is defined as development of multiple perifollicular macules of repigmentation, or, in the case of small (<2 cm) lesions, contraction in size. However, if after 4–6 months or 30–50 treatments they do not respond, PUVA should be terminated. Locations such as lips, distal dorsal hands, fingers and toes, palms, soles and nipples are very refractory to treatment, as are large areas with only white hairs. Stable disease (for at least a year) is usually easier to treat. Duration of disease before PUVA therapy does not affect response rate.[3,15]

Completely repigmented areas can be stable for a decade or more without relapse. But if a lesion is not fully repigmented, reversal of acquired pigmentation may occur when treatment is discontinued.[15]

KUVA and topical PUVA are alternatives to oral PUVA. KUVA uses khellin as a photosensitizer and this is not phototoxic. Topical PUVA may be suitable for few and small lesions.[15] UVA alone is of limited benefit.[15]

UVB Although the action spectrum for phototherapy of vitiligo is not known,[15] UVB, in particular NB-UVB, is currently more often used than PUVA because it has been shown to be at least as effective and possibly safer.[45,46] As for PUVA, it is not very effective in certain anatomic areas (hands and digits, feet and toes) and treatment should be ceased if patients do not respond.[23] Excimer laser should be considered as a therapeutic option for localized lesions.[47]

Pediatric Population: In children, NB-UVB is the preferred phototherapeutic option owing to potential increased cancer risks associated with PUVA. However, PUVA can also be used in children older than 12 years of age.[37]

Atopic Dermatitis

Phototherapy of Acute, Severe Atopic Dermatitis UVA1 phototherapy is a highly effective monotherapy for a limited period of time (ten to 15 exposures), particularly in cases of acute, severe atopic dermatitis.[48] It should not be used for maintenance therapy or for patients under the age of 18 years because its long-term effects are not known.[23] The effectiveness is dose-dependent, with high-dose UVA1 being more efficient than UVA/UVB phototherapy.[49]

Phototherapy of Chronic, Moderate Atopic Dermatitis BB-UVB, combined UVA/UVB, broadband UVA, low-dose UVA1 and, in particular, narrow-band UVB phototherapy are effective treatments in mild and moderate atopic dermatitis and they are generally used in combination regimens with topical steroids. They are relatively safe when used over extended periods of time for long-term management.[23]

NB-UVB and UVA/UVB phototherapy are superior to BB-UVB, broadband UVA or low-dose UVA1.[23] However, in a small number of children, BB-UVB may be less irritating and more effective than NB-UVB because it requires smaller doses to achieve minimal erythema and lymphocyte apoptosis.[37] The excimer laser can also be used to treat localized lesions of atopic dermatitis with faster clearance after fewer treatments compared with traditional NB-UVB or BB-UVB phototherapy.[50]

After NB-UVB, the microbial population in atopic dermatitis patients is similar to control patients,[51] but it is unknown whether this translates clinically into reduced skin infections requiring antibiotics or decreased pruritus.[37]

PUVA PUVA can also be used to treat atopic dermatitis, but a high number of treatments are usually required and recurrences are high and rapid. Long-term treatment should be avoided.[15]

Lichen Planus Oral and topical PUVA are therapeutic options for extensive lichen planus (LP).[3,15] However, LP is usually more resistant than psoriasis, requiring more treatment sessions and higher cumulative UVA doses, with earlier relapses.[3] Combined PUVA-retinoid therapy may accelerate clearing.[3] Postinflammatory hyperpigmentation should be a potential concern. Besides, LP exacerbation during PUVA therapy has occurred in a few patients.[15]

NBUVB therapy can represent an effective option for refractory generalized LP according to a study of 16 patients in which complete response was achieved in 56.25% at 30 sessions and in 68.75% at 40 sessions, confirming the presence of significant correlation between session numbers and improvement of response, that had already been found in previous studies.[52]

A study of 28 patients, 15 treated with oral PUVA and 13 with NB-UVB, concluded that even though oral PUVA produces a better initial clinical response rate, both oral PUVA and NB-UVB are effective treatments for LP, producing similar long-term outcomes.

Graft-versus-host Disease Currently, PUVA represents the mainstay for phototherapy of graft-versus-host disease (GVHD).[15] It has been initially evaluated for lichenoid GVHD owing to clinical and histologic similarities with lichen planus, and it can clear or improve chronic and acute disease.[53,54] In sclerodermoid GVHD, results are controversial.[3,15] Effects may be systemic because mucosal lesions respond to treatment, but there is no improvement in other organs.[3,15] Patients should be followed-up for cutaneous tumors because there seems to be an overall increased risk of malignancies in bone marrow/stem cell recipients, independent of PUVA.[3,15] UVA1 therapy is also promising for the treatment of chronic GVHD, in either of its lichenoid or sclerodermoid variants.[44,55] UVB therapy has been described in a limited number of patients.[15]

Pityriasis Lichenoides PUVA seems to be more effective than UVB in pityriasis lichenoids, especially in the acute form of the disease, where it has been recommended as the phototherapy of choice.[15] In pityriasis lichenoides chronic, PUVA may be reserved for cases of that are UVB resistant.[15] The experience with UVA1 is limited[56] and further investigation is needed.

Urticaria Pigmentosa

PUVA In cutaneous mastocytosis, PUVA therapy results in improvement of skin lesions,[57] but in most patients these recur 5–8 months after treatment discontinuation.[3] Response rate in relapses is though similar to initial lesions.[3] Systemic symptoms such as histamine-induced migraines and flushing also respond to PUVA.[57] PUVA therapy should be considered for patients in which disease is causing severe distress.[3]

UVA1 Cutaneous mastocytosis has also been demonstrated to respond to UVA1 therapy, in its skin and systemic manifestations.[58,59] In a study of four patients, there were no recurrences more than 2 years after cessation of high-dose UVA1 therapy.[59]

Photodermatoses Phototherapy of patients with polymorphous light eruption (PMLE) induces tolerance to sunlight in a process known as hardening. Involved mechanisms include epidermal thickening, pigmentation and probable immunologic effects.[3,15]

PUVA is the most effective preventive treatment in PMLE,[3] but NB-UVB is currently the phototherapeutic option of choice, with recent studies showing that it is an effective alternative to PUVA.[60]

With PUVA, 70% of patients develop hardening with a 3–4-week course treatment of 2–3 sessions a week in early spring. Patients remain protected if they have regular sunlight exposures. However, patients may remain protected for 2–3 months even after pigmentation has faded.[3,15]

Patients with other photodermatosis, including actinic prurigo, hydroa vacciniforme and erythropoietic porphyria, may benefit from NB-UVB[61] or PUVA.[3,15] In solar urticaria, PUVA therapy appears to be the most effective therapy available.[3] Single UVA irradiation of quadrants of body surface hours before PUVA treatment may be useful when patients develop urticarial lesions in the beginning of treatment.[3] In therapy-resistant forms of solar urticaria, rush-hardening consists of multiple daily UVA irradiations at 1-h intervals, providing protection within 3 days.[62] Unlike PMLE, extended treatment may be required in solar urticaria and chronic actinic dermatitis.[3]

Morphea, Scleroderma & Other Sclerosing Skin Conditions Morphea was shown to be effectively treated by UVA1 photherapy in a dose-dependent manner.[63] Medium-dose UVA1 seems to be superior to low-dose UVA1 or NB-UVB.[64,65] The existing evidence indicates that medium–high dose UVA1 therapy delivered over 24–30 treatments can provide significant benefit to patients with morphea, particularly linear and plaque subtypes of disease.[44] UVA1 is likely ineffective in burned out atrophic lesions, deep morphea, Parry Romberg/facial hemiatrophy and eosinophilic fasciitis owing to the depth of the pathology, and systemic treatment should be considered as first-line therapy in these cases.[44] Little to no adverse effects have been reported with this therapy.[44]

UVA1 might also be effective in treating patients with systemic sclerosis, studies to date showing improvement in hand/forearm disease, with a decreased hand score after treatment.[66]

Localized scleroderma and pansclerotic morphea have also been successfully treated with bath PUVA and oral PUVA.[67,68] In our center we have a good experience with topical PUVA for localized scleroderma and we consider this modality worth a try.

Lichen sclerosus has shown to be responsive to UVA1, in both genital and nongenital disease.[69,70]

Other Indications

UVB NB-UVB was found to be an effective treatment in severe cases of seborrheic dermatitis, although flares may occasionally occur.[71]

It has been shown that NB-UVB is effective in controlling uremic pruritus.[72] Although it can also be beneficial in other forms of pruritus, such as idiopathic or that associated with liver disease or diabetes,[15] we have better results in uremic pruritus.

PUVA The experience with PUVA in lymphomatoid papulosis is limited to a few successful anedoctal cases.[73]

PUVA has been used in pityriasis rubra pilaris, but results are inconsistent.[15,23]

Generalized granuloma annulare has been reported to clear completely, but long-term maintenance treatment was required to maintain remissions.[74]

Uncontrolled studies of PUVA treatment for alopecia areata, using all types of PUVA (oral or topical psoralen, local or whole body UVA irradiation), report success rates of up to 60–65%,[75] which are in accordance to our experience. Continued treatment might be needed however to maintain hair growth because relapse rates are high.[75] 308-nm excimer has also been reported as effective.[76,77]

UVA1 Dyshidrotic hand eczema has been treated effectively with UVA1 therapy.[78] Long exposure to low-dose UVA1 might be beneficial for patients with systemic lupus erythematous, with decreased fatigue, joint pain, malaise, stiffness and mouth ulcers, lasting over 3 years.[79] UVA1 therapy has also been shown to improve subacute cutaneous lupus erythematosus lesions, but not those seen in discoid lupus erythematosus.[44] A consensus statement by the North American Rheumatologic Dermatology Society has recently confirmed the potential beneficial effects of UVA1 phototherapy in systemic lupus erythematous patients, but acknowledged that further investigation is needed to address its full benefit.[44] In Table 1, we summarize phototherapy's main clinical applications.

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