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Thursday, April 25, 2019

How Phototherapy used in dermatology

Over many centuries, treatment with sunlight or "heliotherapy" was used in the treatment of skin diseases. More than 3500 years ago, ancient Egyptian and Indian healers used the ingestion of plant extracts or seeds in addition to sunlight for treating "leucoderma". Modern phototherapy began with Nobel Prize winner Niels Finsen who developed a "chemical rays" lamp with which he treated patients with skin tuberculosis. However, it took several decades until phototherapy was introduced anew into the dermatological armamentarium. It was the development of photochemotherapy (PUVA) in 1974 that marked the beginning of a huge upsurge in photo dermatology.

History of Photochemotherapy
The Indians and Egyptians in 2000 BC used the pigment-stimulating properties of the psoralen-containing Bavachee plant (Psoralea corylifolia) and Ammi majus respectively for the treatment of vitiligo. But a millennium later, in 1947, Fahmy, an Egyptian pharmacologist, could isolate psoralen compounds from Ammi majus. Parish successfully introduced a treatment combining 8-methoxypsoralen and UVA called PUVA using newly developed Henselar high intensity artificial UVA light. Topical and bath PUVA were reported as early as 1976 but did not gain as much popularity as the oral form.
Ultraviolet radiation is a small component of the electromagnetic spectrum with a narrow band of radiation from 200-400 nm. The UV spectrum is further divided into UVC (200-280 nm), UVB (280-315 nm) and UVA (315-400 nm).

Phototherapy is the therapeutic use of ultraviolet irradiation without exogenous photosensitizer. Photochemotherapy (PUVA) is the combined use of the drug psoralen and UVA radiation to achieve an effect not achieved with the individual components alone. While artificial ultraviolet radiation that allows precise dosing has only been available for the last century, the recognition of the therapeutic effect of sunlight, of which ultraviolet light comprises a proportion, goes back to ancient times.

 The subsequent development of high intensity UV sources with defined spectra facilitated an optimized therapy for psoriasis and led to an expansion of indications for photo(chemo)therapy also in combination with topical and systemic agents. The introduction of extracorporeal photo pheresis in 1987 for cutaneous T-cell lymphoma and of topical photo dynamic therapy widely expanded the therapeutic possibilities in dermato-oncology. 

Phototherapy is most frequently used to manage psoriasis. It is also helpful in the treatment of a multitude of other skin problems, including: cutaneous T-cell lymphoma, vitiligo, lichen planus, granuloma annulare, pityriasis rosea, acne, generalized itching from various causes, diseases of the hands and feet, atopic and other types of eczema.

PUVA Photochemotherapy

Psoralen plus ultraviolet A (PUVA) photochemotherapy is the photochemical interaction between psoralen and ultraviolet A (UVA) (320 to 400 nm) radiation, which has a beneficial effect in psoriasis and other skin diseases.


Psoralen are naturally occurring tricyclic furocoumarin compounds, present in fruits and vegetables such as limes, lemons, figs and parsnips. The derivative most widely used is 8-methoxypsoralen principally of plant origin but it is available as a synthetic drug. 4, 5, 8-trimethyl psoralen (TMP, trioxsalen) which is synthetic is less phototoxic after oral administration and is primarily used for the treatment of vitiligo.

Orally methoxsalen (8-MOP) is absorbed from the gastrointestinal tract and photosensitivity is present one hour after the dose, reaches a peak at about two hours and disappears after about eight hours. [2] The serum half-life of approximately one hour and is rapidly eliminated which prevents photosensitivity. [3] 

When applied locally 8-MOP rapidly penetrates the skin and can be detected in the urine after four hours. The plasma levels of 8-MOP in patients receiving total body topical 8-MOP are comparable to those found during oral 8-MOP ingestion. [4] The plasma concentration of TMP after bath treatment is only approximately 1% of the plasma after oral ingestion.

Principles of PUVA therapy

The rationale for PUVA therapy is to induce remissions of skin diseases by repeated, controlled phototoxic reactions. These reactions occur only when psoralens are photoactivated by UVA.

Sources of UVA radiation

UVA sources commonly used for PUVA therapy are fluorescent lamps or high-pressure metal halide lamps. The typical fluorescent PUVA lamp has an emission peak at 352 nm and emits approximately 0.5 percent in the UVB range. UVA dose are given in J/cm 2 , usually measured with a photometer with a maximum sensitivity at 350 to 360 nm.

Treatment Protocols

Psoralens with sunlight as the source of ultraviolet A-rays is known as PUVASOL. In centers where artificial chambers are not available PUVASOL is the most commonly used mode of treatment.

Here both UVA and UVB in sunlight result in photoaugmentation  and photoaddition.  A major disadvantage of solar irradiation as a light source is the difficulty in quantifying UV light. The total amount of UVA reaching the skin at any one time varies widely depending on the season, time of the day, latitude and conditions of the atmosphere. Other disadvantages are lack of privacy, difficulty in monitoring the dose of ultraviolet rays and in addition to ultraviolet A, ultraviolet B, infrared rays and visible light which are not needed for PUVA therapy may lead to undesirable effects. UVB in sunlight can increase the thickness of epidermis and this makes the sun exposed skin leathery and this may interfere with the effectiveness. Using a solarium and a PMA 120 complete privacy can be provided.  The main advantages of sunlight as a source of PUVA is that it is inexpensive and patient need not travel long distance for treatment.

Topical treatment Application of 8-MOP in creams, ointments or lotions followed by UVA irradiation is effective in limited plaque psoriasis and for palmoplantar disease. It can also be used to induce pigmentation over streaks of residual pigmentation following punch grafting and when other measures fail to induce pigmentation.

Methodology: A lotion containing 0.1 to 1% 8-MOP is applied and exposed to sunlight either immediately or after one to two hours. [8],[9] This treatment is given three to four times weekly with UVA dose being gradually increased. Maintenance dose may be needed.

Among the psoralens TMP is most convenient for topical application because of its weak penetrability.  The penetrated drug makes photo adducts with DNA molecules even if UVA light is given as soon as the drug is painted resulting in significant inhibition of epidermal DNA synthesis. 

Advantages of topical psoralen therapy are that systemic side effects can be avoided. The disadvantages are that topical PUVA is laborious and time-consuming, if every lesion has to be treated individually. The formation of erythema and blisters is more common with topical psoralen application and intense irregular pigmentation may be seen at the site of treated plaques.

Bath water delivery of 8-MOP and trioxsalen

Bath water psoralen delivery plus UVA has also been found to be equal to or better than local application of psoralen with ointments, creams or lotions.

Psoralen bath delivery eliminates the laborious application required with other topical modalities. The even skin distribution delivered by bath water leads to even pigmentation. Bath water delivery of 8-MOP was found to be as effective as oral administration of 8-MOP and required smaller amounts of UVA radiation and yielded fewer side effects.

Methodology: Bath solutions are prepared by diluting 50 ml of 8-MOP in 100 liters of bath water resulting in a final concentration of 3.75 mg/L. Patients soak for 15 min in this solution and then quickly wipe dry. Immediately patients are given whole body irradiation with UVA, the initial dose depending upon the skin type.

Bath-suit delivery of psoralen

In India, use of bath tub is not in vogue and water problem is perennial and most of the attending patients are poor. Hence bath suit therapy is another alternative therapy found to be an effective therapy for psoriasis. Advantages of bath-suit delivery of 8-MOP are that it requires only two liters of water and 0.8 ml of 8-MOP solution when compared to bath water therapy which needs 100 liters of water and 50 ml of 8-MOP. The cost of the drug is less and it is easy and less time-consuming with no systemic side effects when compared to topical psoralen therapy.

This treatment can be carried out at home with sunlight as the UVA source.

Disadvantage of bath-suit delivery are that the entire body surface especially face does not come in contact with the drug and the concentration of the drug may not be uniform in the bath suit.

PUVA turban therapy

This therapy has been used in the treatment of alopecia areata.

Methodology: A cotton towel is soaked with a 0.0001% 8-MOP solution (1 mg/L) at 37 degrees C, wrung gently to remove excess water and wrapped around the patient's head in a turban fashion for 20 min. This is directly followed by UVA radiation. Treatment sessions are three to four times per week. This therapy has been shown to be a well-tolerated and is an efficient therapeutic alternative in the treatment of alopecia areata.  

Oral treatment

In oral PUVA, 8-MOP is administered orally (0.6 to 0.8 mg per kilogram body weight) 1 to 3 h before exposure, depending on the absorption characteristics of the particular drug brand. The usual dosage for 5-MOP is 1.2 to 1.8 mg per kilogram body weight.

The initial UVA doses are established by either skin typing  or by MPD testing.  Doses are 4, 4.5 or 5 for skin over body and 5 or 6 J/cm 2 for palms and soles. The MPD is defined as the minimal dose of UVA that produces a barely perceptible, but well-defined, erythema when template areas of the skin are exposed to increasing doses of UVA ranging from 0.5 to 5 J/cm 2 . Erythema readings are performed 72 h after testing, at which time the psoralen phototoxicity reaction usually reaches its peak. The MPD test should be performed on previously nonexposed skin (e.g. buttocks). It is difficult to determine MPD in the Indian skin and therapy is started with a starting dose of 0.5 J/cm 2 and increments can be made every second or third sitting.

Repeated exposures are required to clear PUVA responsive diseases and the frequency of treatments is reduced after satisfactory clearing of disease and the last UVA dose is used as a maintenance dose if maintenance treatment is planned. The duration of this maintenance phase and the frequency of treatments depend on the particular disease being treated and its propensity to relapse.

Eye protection with UVA-blocking glasses (B2 Toric glasses) is required from time of exposure to psoralen until sunset that day A sunscreen with an SPF of at least 15 is required for protection from a psoralen phototoxic reaction. Men should also shield their genitalia.

Diseases Treatable by PUVA Therapy

Alopecia areata
Atopic dermatitis
Cutaneous T-cell lymphoma
Dyshidrotic eczema
Graft versus host disease
Lichen planus
Palmophantar pustulosis
Pityriasis lichenoides
Polymerphous light eruption
Pityriasis rubra pilaris
Urticaria pigmentosa

Side effects and contraindications
Because PUVA therapy is based on photosensitizing effects, it is contraindicated in patients with photosensitive diseases such as systemic lupus erythematosus and porphyria cutanea tarda. PUVA therapy is also contraindicated in pregnant women PUVA, because of concerns about possible teratogenicity therapy has both acute and chronic side effects. Acute effects include sunburn reactions, nausea, pruritus, headache and dizziness.

The most common chronic side effects of PUVA therapy include premature photoaging, pigmented macules, actinic keratoses, squamous cell carcinoma, basal cell carcinoma and, possibly, anterior cortical cataracts.


Types of UVB

Two types of UVB phototherapy are available: narrowband and broadband and the principles underlying these treatments and protocols used are different.

Therapeutic spectrum

A potential advance in UVB-based phototherapy has been the introduction of fluorescent bulbs (Phillips model TL-01) that deliver UVB in the range of 310 to 315 nm, with a peak at 312 nm. It has a relatively narrow spectrum of emission and results in a reduction in erythemogenic wavelengths in the 290-305 nm range and 5-6 fold increased emission of the longer UVB wavelengths, thereby resulting in a higher phototherapy index for psoriasis.

Mechanism of action

In psoriatics, NB-UVB phototherapy lowers peripheral natural killer cell activity, lymphocyte proliferation and immune regulatory cytokine production, by both Th1 (IL-2, IFN-g) and Th2 (IL-10) T-cell populations. In vitiligo, it results in stabilization of the depigmenting process the stimulation of residual follicular melanocytes.  

Dosing schedule
Prior to phototherapy, the patients minimal erythema dose (MED) must be determined in order to establish the optimal dosage schedule. MED is determined by standard method.  A template with 20 apertures (10 on each side) of 1½ × 1½ cm 2 is made over the back of a cotton suit used by operation theatre staff. Cotton flaps made over the apertures enables to either shut or keep the apertures open by using Velcro The source of NB - UVB is whole body phototherapy unit with 24 Philips TL-01 bulbs. To determine MED a single panel in the whole body unit with 6 bulbs is used. BB-UVB phototherapy panel with 8 bulbs is used to determine MED to BB. The irradiance from the source is determined using photometer. All the apertures are kept open and back-irradiated with 5 mJ of BB-UVB. One aperture is closed and remaining apertures are closed one after the other after delivering 5 mJ more than the previous aperture. Same procedure was repeated on the other half of the back starting with 50 mJ of NB - UVB and increasing the dose by 50 mJ for each aperture. The dosage schedule for BB - UVB (in mJ) was 5, 10, 15, 20, 225, 30, 35, 40, 45, 50 and for NB - UVB (in mJ) was 50, 100, 150, 200,250, 300, 350, 400, 450, 500. The readings were taken 24 h after exposure. For 311-nm therapy, the initial dose should be 70% MED in the interest of safety. The authors recommend that MED should be determined before NB-UVB therapy for all condition except vitiligo. Patients are treated three to five times per week. Although more sittings will be beneficial, two or three sittings are more cost effective and hence more acceptable. If the initial dose is tolerated, a 20 percent incremental increase of the previous dose is used at each visit. When a previous treatment results in erythema no treatment is given in the next schedule. Increments every second or third sitting is also effective (personal observation) possibly because sub erythemogenic dose of UVB is also as effective as erythemogenic dose. Another approach, as commonly practiced in India, involves a standard starting dose (280 mJ/cm 2 ), with stepwise increase (usually 20%) depending upon the patient's erythema response. Since many patients have high MED, the first few sittings will be useless for which the patient will pay and in addition the time for response will increase.

In the photodermatoses, the
 approach is more cautious with only 10% incremental regimen on sun-exposed sites.  In case of mild erythema, the irradiation dose is held constant for subsequent treatments or until resolution of symptoms. The goal of therapy is to achieve persistent asymptomatic erythema. In case of painful erythema with or without edema/blistering, further treatment is withheld till the symptoms subside. After resolution of overdose symptoms, the dose administered is 50% of the last dose and subsequent increments should be by 10%. We would like to add a note that the percentages of increments are only recommendation and the physician should be guided by his own experience, patient's comfort and increments can be tailored on case to case basis.

UVB burn is unpleasant and if it occurs during initial phototherapy session the patient is always apprehensive about re-starting therapy. If the MED is detected at 475 mJ, 450 mJ can be considered as MED especially in Indian skin as erythema may not be detectable. If the patient is sedentary female or has sensitive skin or has atopic diathesis then initial treatment can be 50% of MED instead of 75%.


Atopic dermatitis
Other dermatoses

Prophylactic low dose NB-UVB has been found to be useful in various predominantly UVA induced photosensitivity disorders like polymorphic light eruption, actinic prurigo, hydroa vacciniforme and the cutaneous porphyrias by providing a hardening photoprotective effect.

Long term use and adverse effects

In addition to the expected immediate sunburn effects, chronic NB-UVB exposure is likely to increase photoageing and the risk of carcinogenesis. However, according to a dose response model it has been calculated that the long-term risk for carcinogenesis with its use may be less than that of PUVA therapy.  Clinical experience with NB-UVB is limited and currently there is no established safe limit for its maximum safe duration of use in vitiligo. In children, the maximum duration allowed is 12 months.

Broadband UVB phototherapy

High-dose UVB phototherapy using sunlamp bulbs (broadband UVB) was an effective treatment in many patients with psoriasis. High dose means using a treatment schedule aimed at staying close to or above the erythema threshold of the patient throughout the course of treatment.

NB UVB is more effective than BB UVB. Both can cause sun burn but BB is more likely to burn than NB UVB. The advantage of BB is very short duration of exposure and rapid clearance especially in psoriasis. BB is reported to be carcinogenic especially among whites. This may not be true for our skin. No case of BB induced malignancy is reported from India. However since lamps are only manufactured in Western countries and since they have abandoned the use of BB UVB and have stopped manufacturing the tubes we have no choice but to stop using the light which is cheaper unless we manufacture the bulb in India.

Combination Therapy
Phototherapy may be combined with topical or systemic agents to achieve higher clearance rates, longer disease free intervals and a lower carcinogenic risk.  Topical agents. Include anthralin, vitamin D analogues, retinoids, glucocorticoids, emollients, saltwater baths and tar. The combination of either broadband UVB or 311 nm UVB therapy with calcipotriol increases the therapeutic efficacy of phototherapy and reduces the irritation caused by calcipotriol. 

Another combination phototherapy of psoriasis is narrowband UVB irradiation and topical tazarotene gel. The addition of tazarotene broadband or narrowband UVB phototherapy was found to promote more effective, faster clearing of psoriasis when compared to either type of phototherapy alone.

Pretreatment with tazarotene gel three times per week for two weeks before phototherapy significantly reduces the mean minimal erythema dose for UVB and the mean UVA exposure required to induce immediate pigment-darkening. Thus, UVB and PUVA therapy can be initiated at lower doses than usual when used in combination with tazarotene.  

Topical application of emollients alters the optical properties of psoriatic lesions, improve transmission of UVB and leads to increased efficacy.  The systemic use of glucocorticoids in combination with photo (chemo) therapy is limited to special indications, such as generalized pustular psoriasis. Also, combination regimens of UVB therapy with methotrexate or cyclosporine A are not advisable, because both substances increase the possibility of UV-induced skin tumors. Retinoids are the most widely used agents for systemic treatment in combination with phototherapy)

The advantage of combining retinoids and UVB irradiation is two-fold: (1) retinoids exert antipsoriatic effects, which might act synergistically with UVB phototherapy; and (2) they have anticarcinogenic effects and thereby could lower the increased skin cancer risk resulting from long-term UVB therapy. Combination regimens with broadband UVB or oral retinoid therapy together induced improvement in psoriatic patients more quickly than with phototherapy alone and reduced the number of treatments and cumulative UV doses.  Similar results were obtained when acitretin, the major metabolite of etretinate, was used in combination with broadband UVB or 311-nm UVB therapy.

Combinations of psoralen, UVA and UVB

Combinations of PUVA and UVB have shown increased efficacy in the treatment of psoriasis. For recalcitrant disease, a combination of PUVA and UVB clears psoriasis more rapidly than PUVA or UVB, buttressing the concept that UVB and PUVA have different and perhaps complementary mechanisms. Similarly, 311-nm exposure enhances the phototoxic activity of bath-PUVA. Bath-PUVA with nbUVB clears psoriasis with fewer exposures and lower cumulative UVA doses under the same minimally erythemogenic conditions.  

Psoralen has not been shown to add to the efficacy of narrow-band UVB in the treatment of vitiligo. 

Although PUVB and nbPUVB are efficacious in the treatment of skin disease, neither has established a utility over nbUVB or PUVA alone. The long-term safety of PUVB or nbPUVB remains to be defined. Further evaluations of psoralen and UVB need to be conducted.

UVA-1 phototherapy

Conventional UVA1 treatment emits wavelengths mainly between 340 and 400 nm, but may also produce scattered radiation >530 nm including infrared irradiation (780-3000 nm). It may be accompanied by extensive heat load predominantly generated by infrared irradiation (780-3000 nm) and/or insufficient cooling systems of the phototherapy devices. UVA-1 phototherapy is quite expensive and requires a special light source not readily available everywhere. It is used for the treatment of scleroderma, chronic GvHD, extragenital LSA or sclerodermoid rarities and other disorders affecting the connective tissue.  It is also effective in the treatment of inflammatory skin diseases such as acutely exacerbated atopic dermatitis, urticaria pigmentosa and disseminated granuloma annulare. 

Excimer lasers

Excimer 308-nm laser is a laser light source that delivers a specific wavelength (308 nm) of UVB radiation. This is beneficial in the treatment of psoriasis. The UV ray generated by the excimer laser focuses on the psoriatic lesion. The advantages are that healthy skin surrounding the areas of psoriasis is not exposed to radiation; higher dose of radiation can be used to induce a visible reaction in the psoriatic plaque Most clinical studies on the use of excimer laser therapy have focused on patients with localized psoriasis involving less than 10 or 20% of the body. It is used to treat a select group of patients with localized, refractory plaque psoriasis (e.g. patients with thick, scaled plaques on the knees and elbows, which are resistant to any conventional treatment).  Side effects include erythema, blisters, hyperpigmentation and erosions. Although the risk from excimer laser therapy is unknown, research to date suggests it is less risky than narrowband UVB as it does not expose the whole body to UV radiation.

Photo dynamic Therapy
Photodynamic therapy (PDT) aims to destroy the desired target selectively, thereby avoiding or minimizing damage to vital structures. The photodynamic reaction consists of the excitation of photosensitizers (mainly porphyrins) by visible light in the presence of oxygen, resulting in the generation of reactive oxygen species, particularly singlet oxygen. These reactive oxygen species mediate cellular and vascular effects depending on the tissue localization of the photosensitizer. This results in a direct or indirect cytotoxic effect on the target cell.  In dermatology, PDT has been used effectively for precancerous and malignant conditions such as actinic keratosis, basal cell carcinoma, Bowen's disease and superficial squamous cell carcinoma, as well as for inflammatory dermatoses such as psoriasis or localized scleroderma.

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