PUVA THERAPY IN DERMATOLOGY

F.Fatemi,MDIsfahan university of medical sciences

DEFINITION

PUVA is a kind of photo-chemotherapy using the sensitizing effects of the drug psoralen :

is applied or taken orally to sensitize the skin, then the skin is exposed to UVA.

Psoralens are photosensitizing agents found in plants.

SEVERAL CUMARINS ARE USED FOR PUVA

8-MOP 5-MOP 4,5′,8- trimethoxypsoralen (as well as the traditional 8-MOP for

bath PUVA ) Oral psoralens are metabolized in the liver within 24 hr. The metabolites are excreted via the kidney. The psoralens allow a relatively lower dose of UVA to be used. When they are combined with exposure to UVA in PUVA, they

are highly effective

CHOOSING THE PROPER UV DOSE FOR PUVA

European clinics test the skin before the treatments, by exposing a small area of the patient's skin to UVA, after ingestion of psoralen.

The dose of UVA that produces uniform redness 72 hours later, called the minimum phototoxic dose (MPD) becomes the starting dose for treatment.

However others (Americans) uses the skin-type–based PUVA protocol .

choose a dose based on the patient's skin type. The dose will increase in every treatment until the skin starts to respond.

ORAL PUVA THERAPY

In the United Statesand in Europe, 2 slightly differing protocols of oralPUVA were Evaluated . in these trials both proved their efficacy.

COMPARISON OF EUROPIAN & AMERICAN PROTOCOLS

Although equally efficient in clearing psoriasis, the American scheme needs 25% more UV exposures and almost 8 weeks more of continuous therapy resulting in a 2.5-fold higher cumulative UV-A dose until remission is achieved.

Therefore, newer guideline sencourage the use of the safer European protocol instead of the American one, although precise determination of MPD is a difficult in very dark-skinned individuals.

Despite such recommendations and because of the time saving aspect, however, the skin-type–based PUVA protocol still has a lot of followers

Phototoxic reactions are delayed, with an erythema reaction peaking 48 to 72 hours after irradiation. Therefore, accurate UVA dosimetry is distinctly required for PUVA therapy as overdosage can easily lead to skin necrosis.

Sometimes, the patient's extremities (in particular the lower extremities) arc exposed to higher doses than the trunk.

Note :

UV PHOTOTHERAPY & PUVA RESPONSIVE DERMATOSIS

PUVA THERAPY IN PSORIASISPUVA THERAPY IN PSORIASIS

Localized PUVA Localized psoriasis of hands and feet (hand/foot unit) Localized disease not responding to other modalities of

therapy Systemic PUVA

Psoriasis involving >20% body surface area Unresponsiveness to topical therapy

.

SYSTEMIC PUVA AS A EFFECTIVE MODALITY IN THE TREATMENT OF PSORIASIS

Guttate and seborrheic (minimally elevated) forms of psoriasis respond most favorably and rapidly to broadband UVB, while chronic, plaque type is more resistant.

PUVA has proven its efficacy in virtually all subtypes of psoriasis Only generalized pustular psoriasis and erytherodermic

psoriasis are difficult to treat with PUVA alone and normally need a combination therapy with retinoids (Re -PUVA)

Despite its proven efficacy, broadband UVB is certainly inferior to PUVA, both in terms of clearing

efficiency and duration of remission.

Oral PUVA therapy should be continued until the plaques are not palpable anymore and scaling and intrinsic erythema are gone.

PIP is no indication for continuing treatment.

In general no maintenance therapy should be done . Some authors argue, however, that patients with more aggressive

disease should be subjected to a maintenance therapy once weekly for 2 months in to assess the course of the response further.

SIDE EFFECTS OF ORAL PUVA

Early & Late effects

EARLY EFFECTS

Oral PUVA is generally well tolerated; however, a number of potentially serious side effects exists :

Phototoxic reactions : a prodromal state with general malaise and itch precedes the rash.

GI symptoms (ie, nausea and vomitus) are not uncommon but can often be improved by intake of 8-MOP with some food , especially milk.

Rarely, increase in transaminase levels in the liver, and, thus liver function tests should routinely be performed before starting oral PUVA.

LATE EFFECTS PUVA in the long term leads to a photoaged skin pattern

with elastosis, poikiloderma, and lentigines. Of concern is the induction of NMSCs , which is proven and

occurs in more than 25% of PUVA-treated patients. Whether melanoma can be induced by PUVA has not been

clarified.

All patients who received several course of oral PUVA should enter a long-term-follow up program for at least

25 years

THE RISK OF CARCINOGENICITY ,PUVA VS UVB

There is an increased risk of skin cancer following PUVA, shown by both US and European studies. The greater risk measured by the US studies may be at least partly explained by high UVA dose exposure and the lighter phototypes of the patients.

The lack of prospective studies in psoriasis patients treated with NB-UVB constitutes a barrier to the robust assessment of carcinogenic risk of this phototherapy technique.

LATE EFFECTS CONT..

Eye problems : Because psoralens bind to the proteins in the lens , there is

further risk for cataract evolution under PUVA therapy. In addition , damage to the retina could also be possible due to

the photo-oxidative reactivity of psoralens passing through the retinal vessels.

Therefore, eye protection has to be worn for at least 12 hours after PUVA

Studies have not shown an increased incidence of cataracts under eye protection, so this preventive measure seems

to achieve the desired effect.

ABSOLUTE CONTRAINDICATIONS :

Genetic dermatosis characterized by photosensitivity or high risk for skin cancers(UVB,PUVA)

Treatment with cyclosporine (UVB,PUVA) Previous history of skin cancer if current cancer ,especially SCC& MM

(UVB,PUVA)

High cumulative number of PUVA treatment (>150-200 individual treatments) (PUVA)

Pregnancy or lactation (PUVA) Child's age (young children) (PUVA)

RELATIVE CONTRAINDICATIONS

Previous history of arsenic exposure, ionizing radiation (UVB,PUVA) Immunosupressive medication (UVB,PUVA) Atypical melanocytic nevi (UVB,PUVA) Seizure disorder,risk of fall/injury (UVB,PUVA) Poor compliance (UVB,PUVA)

Men & women in reproductive age without contraception (PUVA) Impaired liver function or hepatotoxic medications(PUVA) Cataract(PUVA)

NEED TO ADJUST DOSE OR MONITOR CLOSELY

Skin type 1 (UVB,PUVA) Photosensitive dermatoses (UVB,PUVA) Unavoidable systemic or topical phototoxic medications

(UVB,PUVA) Vitiligo (UVB,PUVA)

possible interactions with medication : warfarin(PUVA)

PRE PROCEDURE RECOMENDATION

Advisable is to have : eye examination LFTs RFTs ANA ,anti-Ro antibody

PRECAUTIONS DURING PUVA THERAPY PRECAUTIONS DURING PUVA THERAPY

UV-blocking goggles are used to protect the eyes.

If treatment is not required for facial involvement, the face is protected either by use of a broad spectrum sunscreen with an SPF of 50+ or a cloth barrier.

Male genitalia are protected with the use of underwear or an athletic supporter

If PUVA is to be given to the genitalia, exposure at 25% of the ideal dose can be safely undertaken

PRECAUTIONS AFTER PUVA THERAPY PRECAUTIONS AFTER PUVA THERAPY

Patients must protect their eyes after ingesting psoralen. Wraparound UV-blocking glasses, which give complete UVA photoprotection should be worn when the patient is exposed to sunlight, from the time methoxsalen is ingested until sunset

Sun avoidance is advised to minimize pigmentation from natural sunlight. Excessive pigmentation may ultimately limit the effectiveness of PUVA therapy and require higher doses of UVA.

The skin should be protected from natural sunlight through appropriate clothing and avoidance

The amount of UVA emitted by common fluorescent lights is insufficient to activate psoralens. Thus, photoprotection is not required in home or office settings.

BATH PUVA THERAPY

BATH PUVA THERAPY

Several studies rated bath PUVA equally or even better than systemic PUVA

Advantages : the lack of GI and hepatic side effects No need for eye protection.

Disadvantages : higher running costs due to greater complexity of the procedure Low patient adherance Bathwater PUVA is not

undertaken during pregnancy or breast-feeding.

0.5-1 mg/L 8-MOP , 0.33 mg / L TMP Start with 0.3 MPD Perform 2-4 irradiation /Wk Immediate irradiation after bathing ,constant 37°C

temperature in the PUVA bathwater. In some publications, trimethylpsoralen is preferred over 8-

MOP as the agent to add to the bathwater because of its much higher photosensitizing capacity

Bathing the patient on a foil in a bath that is wetted with roughly 10 L of 8-MOP containing warm water

Sheet bath PUVA

medisun Balneo 2000 was developed specially for brine and PUVA-foil baths with subsequent UV radiation..

How it works:The patient lies in the bath solution separated from the bath water by the foil (e.g. 5 liter brine or Meladinine solution). The pressure of the bath water from all sides ensures an even film of fluid on the patient

Acute side effects such as phototoxic reactions, pruritus occur in the same proportion as with oral PUVA.

A large study that found that bath PUVA carries a lower risk of skin cancer development in the long term than oral PUVA.

The photo carcinogenic potential of PUVA is dose related & because bath PUVA requires smaller cumulative UVA doses than systemic PUVA, the cumulative risk must be lower for this treatment modality.

SIDE EFFECTS OF BATH PUVA

LOCAL BATH PUVAPUVA bath can be used to treat local disease spots, particularly palms and soles, without exposing the rest of the body.

The skin is gently dried off. Some centres recommend a waiting period of 15 to 30 minutes while the solution penetrates into the skin, whereas others treat immediately.

The affected skin is exposed to UVA emitted from special fluorescent lamps.

The treated skin should then be covered for the next 2-3 days, especially when outdoors, to protect it from inadvertent exposure to UVA.

PUVA THERAPY IN VITILIGOPUVA THERAPY IN VITILIGO

Topical PUVA Localized disease

Systemic PUVA Vitiligo involving more than 10% body surface area Patients with localized disease not responding to

topical PUVA or other modalities of treatment

TOPICAL PUVA IN VITILIGOTOPICAL PUVA IN VITILIGO

Topical PUVA with 8MOP may be used in patients with smaller lesions involving less than 5% of body surface area.

0.01-0.1% 8MOP in a cream or lotion base is applied to the affected area and irradiation is done after 30 min.

A weekly increment of 0.25 J/cm 2 or by 20% of the previous dose is given till onset of erythema.

Application of sunscreen to the surrounding uninvolved skin can prevent undue tanning.

TMP and 5MOP are more phototoxic topically.

PATIENT SELECTION FOR SYSTEMIC PUVA IN VITILIGO

Darker skinned people respond better than those who are fair skinned.

Head and neck lesions and lesions on hairy parts of the body respond best.

lips, dorsae of hands, acral parts, bony prominences, palms, soles, and nipples are refractory to treatment.

Segmental vitiligo may or may not respond. Duration of disease does not affect the response rate to PUVA.

PATIENT SELECTION FOR PUVA IN VITILIGOPATIENT SELECTION FOR PUVA IN VITILIGO

This treatment seldom achieves extensive repigmentation that is cosmetically acceptable

Treatment response is often followed by relapse Response is denoted by the occurrence of perifollicular

repigmentation and 70% cases respond within 12-24 weeks. If there is no response even after approximately 50 sessions, PUVA should be discontinued

Patients with vitiligo affecting more than 30-40% body surface area (BSA) do not respond well to medical therapy.

PATIENT SELECTION FOR PUVA IN VITILIGOPATIENT SELECTION FOR PUVA IN VITILIGO

For optimal and maximum pigment induction, prolonged therapy lasting for months is required with as many as 100-200 exposures given 2-3 times a week

If response occurs and patient discontinues treatment, the newly acquired repigmentation may be lost.

Completely repigmented areas may remain stable for more than 10 years.

PUVA VS UVB IN VITILIGO NUVB phototherapy is now used more commonly than PUVA since it does

not require the use of the Psoralen.

NBUVB does not cure the legs and hands, compared to the face and neck. To the hands and legs PUVA may be more effective.

The reason can be because UVA penetrates deeper in the skin, and the melanocytes in the skin of the hands and legs is deeper in the skin. The Narrowband UVB does not reach the melanocytes

In comparison studies of NUVB with PUVA, narrowband UVB was as effective as PUVA also had: fewer side effects . In a recent randomized double-blind trial of non-segmental vitiligo, NUVB

therapy was superior to oral PUVA therapy and the color match of repigmented skin was

considered to be better in the patients treated with NBUVB.

PUVASOL

PUVASOL stands for psoralen and UVA obtained by solar light

PUVASOL is advised for those patients who cannot visit the hospital for phototherapy.

Disadvantages: 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.

Difficulty in monitoring the dose of ultraviolet rays UVB ,IR and VL, which are not needed for PUVA therapy may lead to

undesirable effects.

UVB in sunlight can increase the thickness of epidermis and makes the sun-exposed skin leathery and may interfere with the effectiveness of light therapy.

According to a study conducted by Balasara swathy et al., the best time of the day for PUVASOL is between 9.15-11.15 a.m. and 2.30-3.30 p.m.

There is minimal unwanted exposure to UVB and infrared light at these times.

SYSTEMIC PUVASOL IN PSORIASISSYSTEMIC PUVASOL IN PSORIASIS

In two Indian studies, nearly 55% and 63% of patients have shown good to excellent improvement with PUVASOL in psoriasis.

8MOP in the dose of 0.6 mg/kg body weight is administered after breakfast. Nearly 1.5-2h later, sun exposure is advised for 10 min.

Treatment is carried out 2-3 times/week and time of exposure is increased by 5 min every week till a maximum of 30-45 min.

Use of eye protective glasses and avoidance of further sun exposure for the next 8h is to be followed to prevent eye toxicity and darkening of the normal skin.

TOPICAL PUVASOL IN PALMOPLANTAR PSORIASISTOPICAL PUVASOL IN PALMOPLANTAR PSORIASIS

Dilute 1 cc of 8-MOP 0.1 % in 1 lit tap water then soak hands and/or feet in thissoltion for 15 min and then be expose immediately to sun light for 15 min.

3-4 s/w Also indicated for palmoplantar LP or hyperkeratotic palmoplantar

eczema

After puvasol wash the skin area and put zinc oxide or sunscreen for the remaining of the day.

SYSTEMIC PUVASOL IN VITILIGOSYSTEMIC PUVASOL IN VITILIGO

In vitiligo, oral TMP is preferable to 8MOP due to its weaker phototoxic effects.

Treatment should be given twice to thrice weekly, with a minimum gap of 1 day between treatments.

The duration of sun exposure is to be increased weekly until there is mild erythema of the involved area after which, that time can be kept constant.

If there is no improvement even after 30-40 sittings, it should be discontinued.

TOPICAL PUVASOL IN VITILIGOTOPICAL PUVASOL IN VITILIGO

Though topical PUVASOL is generally avoided due to the greater phototoxic risk and frequent occurrence of painful blisters, it may be tried during rainy season

A total of 0.1% 8MOP is applied carefully over the vitiliginous patches (one part of commercially available 8MOP lotion can be diluted with nine parts of eau-de-cologne and used). Propylene glycol can also be used as a diluent.

After 30 min, the patches are exposed to sunlight starting with 0.5-1 min. Treatment is done 2-3 times/week and duration of sun exposure should be slowly increased by 0.5-1 min every week till slight erythema appears after which the time is kept constant.