Puva therapy

a full context abt PUVA

1. PUVA THERAPY -M.HIMA.VINUTHNA PG DVL 1 ST YEAR

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

3. PSORALENS? Phototoxic compounds  enter cells  absorb photons  produce photochemical reactions that alters the function of cellular components R esults in beneficial therapeutic effect after repeated controlled phototoxic reactions

4. Route of administration – oral -- topical ( solutions,creams,baths ) Types Methoxalen or 8-methoxypsoralen(8-MOP) Bergapten or 5-methoxypsoralen(5-MOP) Trioxsalen or 4,5,8-trimethylpsoralen(TMP)

5. PHOTOCHEMISTRY

6. 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

7. 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

8. 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

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

10. ULTRAVIOLET-A RADIATION

11. 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

12. 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 - R evert 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

13. PHOTOSENSITIVITY EFFECTS I nflammatory 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

14. 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

15. TREATMENT PROTOCOLS

16. TOPICAL TREATMENT Application of 8-MOP as 0.15% in creams, ointments, or lotions followed by UVA irradiation is effective in clearing psoriatic lesions Disadvantages Nonuniform distribution on skin surface  phototoxic erythema reactions and hyperpigmentation Laborious and time consuming Does not prevent apprearence of new active lesions in previously untreated & unaffected areas Treatment of choice for limited plaque psoriasis and palmoplantar disease

17. 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

18. 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.

19. BATH PHOTOCHEMOTHERAPY

20. 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 T rimethylpsoralen is preferred over 8-MOP as the agent to add to the bathwater because of its much higher photosensitizing capacity

21. INDICATIONS FOR BATH WATER PUVA Psoriasis Scleroderma Mycosis fungoides Urticaria pigmentosa Lichen planus Prurigo nodularis Subacute prurigo

22. 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 : H igher running costs due to greater complexity of the procedure Low patient adherance

23. BATHING SUIT PUVA MATERIALS REQUIRED plastic bucket bathing suit made up of water absorbing material (flannel) rain coat 2 LITRES of water 1 ml of 1% 8-MOP (3.75mg/l) PROCEDURE 2LITRES 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

24. 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.

25. SOAK PUVA MATERIALS REQUIRED Plastic tub 3.75mg/l 8-MOP 2 litres of water PROCEDURE 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.

26. INDICATIONS FOR SOAK PUVA Palmoplantar psoriasis Chronic palmoplantar eczema Palmoplantar pustulosis Lymphomatoid papulosis Twenty- Nail dystrophy Congenital palmoplantar keratoderma

27. TURBAN PUVA MATERIALS REQUIRED Cotton cloth 3.75mg/l 8-MOP 2 litres of water Small Plastic tub PROCEDURE 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

28. INDICATIONS FOR TURBAN PUVA Alopecia areata Chronic GVHD A lopecia

29. Phototherapy-Responsive Diseases Therapy 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

30. PHOTOCHEMOTHERAPY FOR PSORIASIS

31. 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.

32. 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.

33. 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

34. IADVL THERAPEUTIC GUIDELINES FOR INDIAN PATIENTS INITIAL 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 phase Final clearence dose of UVA 5-20 J/cm2 After 1-3hrs Initially 2-3 J/cm2 UVA  0.5 j/cm2 UVA later on

35. 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.

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

37. COMBINATION TREATMENTS Topical Combinations: Topical adjuvant therapies with Glucocorticoids Anthralin T ar 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

38. Cyclosporine: PUVA+ cyclosporine  skin carcinogenesis So, 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

39. PHOTOCHEMOTHERAPY IN VITILIGO

40. 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

41. ORAL PUVA 8-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

42. 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

43. 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 A fter 30 mins

44. 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

45. 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 . 

46. PHOTOTHERAPY FOR ATOPIC DERMATITIS

47. 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

48. PHOTOTHERAPY FOR LICHEN PLANUS

49. 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

50. PHOTOCHEMOTHERAPY FOR URTICARIA PIGMENTOSA

51. 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

52. PHOTOCHEMOTHERAPY FOR GVHD

53. 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 2 nd to 4 th exposure UVA radiation 3-4 times weekly

54. PHOTOCHEMOTHERAPY AS PREVENTION FOR PHOTODERMATOSES

55. 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 T olerance to sunligh t can be increased 10-fold or more after a single treatment course

56. PHOTOCHEMOTHERAPY IN HIV

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

58. PUVA FOR CUTANEOUS T- CEll lYMPHOMA

59. Treatment regimen is same as psoriasis Clearing 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 . C omplete clearing may be induced when the cells are confined to the epidermis and superficial dermis, the depth of effective UVA penetration into the skin

60. CONTRAINDICATIONS FOR PUVA

61. SIDE EFFECTS OF PUVA

62. REFERENCES FITZPATRICKS DERMATOLOGY IN GENERAL MEDICINE BOLOGNIA TEXTBOOK OF DERMATOLOGY IJDVL ARTICLES