PUVA THERAPY

-M.HIMA.VINUTHNAPG DVL 1ST YEAR

DEFINITION

•Photochemotherapy with psoralens combines the use of oral or topical Psoralens (P) and Ultraviolet- A radiation (UVA) = PUVA

PSORALENS?

•Phototoxic compounds enter cells absorb photons produce photochemical reactions that alters the function of cellular components

•Results in beneficial therapeutic effect after repeated controlled phototoxic reactions

•Route of administration – oral -- topical (solutions,creams,baths)

•Types1) Methoxalen or 8-methoxypsoralen(8-MOP)2) Bergapten or 5-methoxypsoralen(5-MOP)3) Trioxsalen or 4,5,8-trimethylpsoralen(TMP)

•PHOTOCHEMISTRY

•Pharmacokinetics

•Important steps between ingestion of a psoralen and its arrival at the site of action include:Absorption First-pass effect Blood transportation Tissue distribution

•Oral psoralens •Metabolised in the liver within 24hrs and excreted via kidney•Peak levels of psoralens in blood is 1-8hrs with a mean of 2 hrs•Photosensitivity is maximal upto 1- 2hrs after ingestion of psoralen•This forms the basic for giving UV radiation after 2 hrs of intake of psoralens

•Liquid preparations of 8-MOP & 5-MOP •Give higher and earlier peak serum levels than crystalline forms•Before reaching skin circulation,they are metabolised during passage through the liver•MOP have serum half life approx. 1hr but the skin remains sensitive to light for 8-12hrs•Despite widespread distribution of the drug throughout the body, it is activated on the skin, where UVA enters

•Topical psoralens when applied to skin they rapidly penetrate and are detected in the urine after 4hrs

ULTRAVIOLET-A RADIATION

•The action spectrum is reported to be between 320 and 400 nm.•Common UVA sources are fluorescent lamps or high pressure metalhalide lamps•Typical fluorescent PUVA lamp has emission peak at 325nm •UVA doses are given in J/cm2, usually measured with a max. Sensitivity at 350-360nm•Although the action spectrum of antipsoriatic activity & phototoxic erythema peaks at 335nm, longer wavelengths have proved equally effective in clearing psoriatic lesions

MECHANISMS OF PHOTOCHEMOTHERAPY

•PSORALENS- Photoconjugation of psoralens to DNA with subsequent suppression of mitosis, DNA synthesis, and cell proliferation revert cell proliferation rates to Normal in Psoriasis . They also stimulate melanogenesis

•PUVA - Revert pathologically altered patterns of keratinocyte differentiation & the no. of proliferating epidermal cells. - Diminishes langerhans cell no’s within epidermis. - Downregulates certain lymphocytes & APC functions - Alters expression of cytokines and cytokine receptors

PHOTOSENSITIVITY EFFECTS•Inflammatory response that manifests as delayed phototoxic erythema, proportional to the dose of both drug and UVA as well as to the individual’s sensitivity to phototoxic reactions. • PUVA erythema appears after 24–36 hours and peaks at 72–96 hours, or even later• Daily PUVA treatments can result in unexpected severe delayed cumulative phototoxicity

•Severe PUVA reactions may lead to blistering and to superficial skin necrosis, Pigmentation•Overdoses of UVA swelling, intense pruritus, sometimes stinging sensation in the affected skin area, possibly as a consequence of damage of superficial nerve endings

TREATMENT PROTOCOLS

TOPICAL TREATMENT•Application of 8-MOP as 0.15% in creams, ointments, or lotions followed by UVA irradiation is effective in clearing psoriatic lesions•DisadvantagesNonuniform distribution on skin surface phototoxic erythema reactions and hyperpigmentationLaborious and time consumingDoes not prevent apprearence of new active lesions in previously untreated & unaffected areas

•Treatment of choice for limited plaque psoriasis and palmoplantar disease

ORAL PUVA• DOSAGE•8-MOP -- 0.6–0.8 mg/kg body weight OR •5-MOP -- 1.2- to 1.8-mg/ kg body weight

Should be administered within 1-3 hrs before exposure depending on absorption characteristics of the particular drug.Liquid drug preparations are absorbed faster and yield higher and more reproducible serum levels than microcrystalline forms

•The initial UVA doses are determined by either the patient’s skin type or by MPD testing•The MPD test should be performed on previously nonexposed skin (e.g. buttocks). •Time-consuming than phototyping, it allows for more accurate and higher UVA doses during initial treatment.

BATH PHOTOCHEMOTHERAPY

• MATERIALS REQUIRED:• 3.75mg/L 8-MOP Or 0.33mg/L TMP in 100 ltrs of

water in a bath tub• Whole body immersion- 15-20mins• Immediate irradiation after bathing.• Perform 2-4 irradiation /Week• Trimethylpsoralen is preferred over 8-MOP as the

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

INDICATIONS FOR BATH WATER PUVA

PsoriasisSclerodermaMycosis fungoidesUrticaria pigmentosaLichen planusPrurigo nodularisSubacute prurigo

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

• Advantages :No GI and hepatic side effects No need for eye protection.The total ultraviolet A dose required for bath PUVA is

3–6 times lower than oral PUVA.

• Disadvantages :Higher running costs due to greater complexity of

the procedureLow patient adherance

BATHING SUIT PUVAMATERIALS REQUIREDplastic bucket bathing suit made up of water absorbing material (flannel) rain coat 2 LITRES of water1 ml of 1% 8-MOP (3.75mg/l)PROCEDURE2LITRES of water + 3.75mg/l 8-MOP in a bucket and soaking of bathsuit in this solution for 5mins pt wears bathsuit with raincoat on top for 15 mins UVA radiation with starting dose 1-2J/cm2

Total of 15-20 treatments required for clearing psoriasis

Advantages

This method requires only 2 litres of water and 1 ml of psoralen solution per treatment•Therapy can be carried out at home with sunlight as the UVA source.

Disadvantages

The entire body surface may not come in contact with the bathing suit•The concentration of psoralen may not be uniform in the bathing suit.

SOAK PUVAMATERIALS REQUIREDPlastic tub3.75mg/l 8-MOP2 litres of waterPROCEDURE•Hands and/or Feet are soaked in a 3.75 mg/L solution of 8-MOP in a small plastic tub or a basin for 20 minutes and then patted dry•After another 30 minutes, the part is exposed to UVA in a hand and foot unit• Treatments are repeated 3–4 times/week•If sunlight is used as the UVA source, the exposure time is 4–5 minutes initially with 1-minute increments every week up to a maximum of 30 minutes.

INDICATIONS FOR SOAK PUVAPalmoplantar psoriasisChronic palmoplantar eczemaPalmoplantar pustulosisLymphomatoid papulosisTwenty- Nail dystrophyCongenital palmoplantar keratoderma

TURBAN PUVAMATERIALS REQUIREDCotton cloth3.75mg/l 8-MOP2 litres of waterSmall Plastic tubPROCEDURE•An absorbent cotton cloth is soaked for 30 seconds in a 3.75 mg/L solution of 8-MOP & gently squeezed to remove excess water and wrapped around the head for 5 minutes. •Repeated 4 times (a total of 20 minutes) and the area is then exposed to UVA or sunlight.If sunlight is used as the source of UVA, exposure starts with 5 minutes, increased by 1 minute with each exposure up to a maximum of 15 minutes.•treatment is given 3–4 times/week for 10–12 weeks

INDICATIONS FOR TURBAN PUVA

Alopecia areataChronic GVHDAlopecia

Phototherapy-Responsive DiseasesTherapy of Disease• Psoriasis• Palmoplantar pustulosis • Mycosis fungoides (stages IA, IB) • Vitiligo• Atopic dermatitis • Generalized lichen planus • Urticaria pigmentosa• Cutaneous graft-versus-host disease • Generalized granuloma annulare• Pityriasis lichenoides• lymphomatoid papulosis • Pityriasis rubra pilaris• localized scleroderma• Morphea

Prevention of disease symptoms• Polymorphous light eruption• Hydroa vacciniformea • Solar urticaria• Erythropoietic protoporphyria• Chronic actinic dermatitis

PHOTOCHEMOTHERAPY FOR PSORIASIS

INDICATIONS FOR PUVA IN PSORIASIS

•SYSTEMIC PUVA•Psoriasis involving >20% BSA•Unresponsiveness to topical therapy

•LOCALIZED PUVA•Localized psoriasis of hands and feet•Localized disease not responding to other modalities of therapy.

EXCLUSION CRITERIA•Children aged less than 10 years. (Although in exceptional circumstances, younger age groups may be considered for treatment provided regular ophthalmologic evaluation is done to rule out ocular toxicity)•Pregnancy and lactation•People suffering from photosensitivity disorders.

PROTOCOLS

Differences btw the US and EUROPEAN protocols for PUVA therapy

US EUROPE

UVA dosimetry

Predetermined dose according to skin phototype

Individualized dose according to MPD determination

Frequency of treatment

2-3 times/week 4times/week

Dose increments

0.5-1.5 j/cm2 0.5j/cm2 each week

IADVL THERAPEUTIC GUIDELINES FOR INDIAN PATIENTSINITIAL TREATMENT (clearence phase) 0.6-0.8mg/kg body weight of oral 8-MOP

2-3 times per week mild erythema moderate- severe erythema

dose reduced/constant treatment deferred 15-25 sittings required for clearence phaseFinal clearence dose of UVA 5-20 J/cm2

After 1-3hrs

Initially 2-3 J/cm2 UVA 0.5 j/cm2 UVA later on

MAINTANENCE TREATMENT•The last dose of clearance phase is kept constant and the frequency of treatment is slowly reduced to as low as once a month.

TREATMENT OF RELAPSES• If significant relapse of the disease occurs after treatment discontinuation or during the maintenance phase, it is appropriate to resume a clearance schedule.• For minor recurrences occurring during the maintenance phase, the frequency of treatments may be increased until disease control is achieved.

PUVASOL 0.6mg/kg body wt of oral 8-MOP 1.5-2hrs sunexposure for 10mins

2-3times/week

sunexposure 5mins/every week max of 30-45mins

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

COMBINATION TREATMENTSTopical Combinations: Topical adjuvant therapies with •Glucocorticoids•Anthralin•Tar preparations•Calcipotriol•Tazarotene

Methotrexate: •PUVA + methotrexate can the duration of treatment, number of exposures, and total UVA dose and is also effective in clearing patients unresponsive to PUVA•safe if used during the clearing phase only•Long term therapy skin cancers

Cyclosporine:PUVA+ cyclosporine skin carcinogenesisSo, the combination is discouraged

Retinoids : •The therapeutic efficacy of PUVA therapy is dramatically increased by daily oral retinoid (etretinate, acitretin, isotretinoin; 1 mg/kg) administration beginning 5–10 days before the initiation of PUVA, and continued throughout the clearing phase•called RePUVA characteristically reduces the number of exposures by one-third and the total cumulative UVA dose > one-half •MOA- accelerated desquamation that optimizes the optical properties of the skin and reduction of the inflammatory infiltrate

PHOTOCHEMOTHERAPY IN VITILIGO

PATIENT SELECTION•Dark skinned people•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.•Patients with vitiligo affecting more than 30-40% body surface area (BSA) do not respond well to medical therapy like PUVA/PUVASOL

ORAL PUVA8-MOP(0.6–0.8 mg/kg body weight) or TMP(3.6mg/kg bw)taken orally

UVA radiation

150-200 sessions in 2 yrs, every alternate day

complete or near-to-complete response

1-3hrs

ORAL PUVASOL Oral TMP( 3.6mg/kg body weight)

sunexposure(0.5-1min)

2-3 times/week

Within 1-3hrs

every week sunexposure 0.5-1min till erythema appears

30-40 sittings no improvement Discontinued

TOPICAL PUVA 0.01-0.1% 8MOP in a cream or lotion base

UVA radiation

2-3 times/week

radiation   0.25 J/cm 2 every wk

After 30 mins

TOPICAL PUVASOL  0.1% 8MOP CREAM or LOTION

Sunexposure (0.5-1min)

2-3times/week

every week sunexposure 0.5-1min till erythema appears

After 30 mins

COMBINATION THERAPY•Calcipotriol and PUVA: Many studies show quicker response to treatment with more intense repigmentation, though acral vitiligo does not respond well. -Concurrent topical calcipotriol may shorten the duration of UVA exposure thus leading to reduction of PUVA-induced side effects •Low dose azathioprine also has been used to improve the efficacy of PUVA in vitiligo. 

PHOTOTHERAPY FOR ATOPIC DERMATITIS

•Treatment guidelines are same as psoriasis•Moderate , severe, erythrodermic forms of atopic eczema can benefit•More difficult to treat, higher number of treatments required•Even if cleared by PUVA, recurrence rates are higher•Combination of PUVA+ corticosteroids better than PUVA alone•MOA- alteration of lymphocytic function in the dermal infiltrate

PHOTOTHERAPY FORLICHEN PLANUS

•Alternative to systemic corticosteroids in generalised lichen planus•More treatment sessions and higher cumulative UVA doses•Side effect- Marked Post inflammatory hyperpigmentation•Combined RePUVA- disseminated and keratotic forms of LP

PHOTOCHEMOTHERAPY FOR URTICARIA PIGMENTOSA

•Temporary resolution of skin lesions probably due to chronic degranulation of the mast cells.

•Treatment results in loss of Darier sign, relief of itching, and flattening and even complete disappearance of cutaneous papules and macules.

•Histamine-induced migraine and flushing improve gradually as treatment is continued

PHOTOCHEMOTHERAPY FOR GVHD

•Acute and chronic cutaneous graft-versus-host disease•Well circumscribed, localized forms respond with softening of the fibrotic, sclerotic connective tissue•But, widespread & disseminated lesions hardly respond.•Increase of the UVA dosage by 0.5 J/cm2 at maximum after every 2nd to 4th exposure•UVA radiation 3-4 times weekly

PHOTOCHEMOTHERAPY AS PREVENTION FOR PHOTODERMATOSES

•Tolerance to sunlight can be induced in several photodermatoses by PUVA therapy

•PMLE- PUVA an effective treatment•3-4 week PUVA course of 2-3 treatments/wk suppress the disease •Only temporary, sunlight required for maintenance phase•MOA- Hyperpigmentation and thickening of the stratum corneum

•Solar urticaria- PUVA an effective preventive treatment•Tolerance to sunlight can be increased 10-fold or more after a single treatment course

PHOTOCHEMOTHERAPY IN HIV

•UV radiation and psoralens Worsen HIV disease•Both UV radiation and psoralen photosensitization activate the HIV promoter boost viral gene transcription virus production

PUVA FOR CUTANEOUS T-CEll lYMPHOMA

•Treatment regimen is same as psoriasisClearing phase Maintenance phase- two exposures per week for 1 month and one exposure per week for another month Follow-up phase- monthly monitoring and later bimonthly

•Remission confirmed by histological examination• Clinical remissions - phototoxic destruction of the malignant lymphocytes that infiltrate the skin.•Complete clearing may be induced when the cells are confined to the epidermis and superficial dermis, the depth of effective UVA penetration into the skin

CONTRAINDICATIONS FOR PUVA

SIDE EFFECTS OF PUVA

REFERENCES

FITZPATRICKS DERMATOLOGY IN GENERAL MEDICINEBOLOGNIA TEXTBOOK OF DERMATOLOGYIJDVL ARTICLES