Phototherapy

various radiations used in phototherapy

1. PHOTOTHERAPY By : Dr. A jeet S ingh

2. PHOTOTHERAPY – It is the use of ultraviolet radiation or visible light for therapeutic purposes. In use today are : N arrowband and B roadband UVB P soralen photochemotherapy (PUVA ) UVA1 phototherapy T argeted phototherapy

3. UNITS OF MEASUREMENT Radiant energy – Amount of radiation. Expressed in joules Radiant power – Rate of delivery of energy. Expressed in watt( J/sec) Irradiance – Radiant power per unit area. Expressed as W/cm2 Exposure dose – Radiant energy delivered per unit area of a given surface area in a given exposure time. Expressed in J/cm2

4. Mechanism of action MECHANISM OF ACTION

5. UVB radiation 290–320 nm A bsorbed by the epidermis and superficial dermis . MECHANISM OF ACTION Produces DNA damage - pyrimidine dimers and pyrimidine- pyrimidone photoproducts. Photochemical changes in trans - urocanic acid, converting it to the cis -form of the molecule. cis- urocanic acid is a mediator of the UVB induced immunosuppression.

6. UVB converts tryptophan into 6-formylindolo[3,2 -b ] carbazole (FICZ ), which binds to the intracellular aryl hydrocarbon hydroxylase (Ah) receptor, initiating a series of events that culminates in activation of signal transduction pathways . Generation of reactive oxygen intermediates , which has downstream effects- DNA damage Lipid peroxidation Activation of signal transduction pathways Stimulation of cytokine production.

7. UVA radiation 320–400 nm. C an reach the mid- or lower dermis . M ore effective than UVB for skin diseases in which the cutaneous pathology lies deeper than the superficial dermis. MECHANISM OF ACTION G eneration of reactive oxygen intermediates. ROI are formed in mitochondrial enzyme complexes during oxidative phosphorylation. C an produce pyrimidine dimers in DNA but less effective than UVB in doing so.

8. UVA-induced oxidants causes - DNA damage Lipids peroxidation S tructural and nonstructural proteins damage O rganelles such as mitochondrial damage The generation of oxidants following UV exposure has been implicated in photoageing of the skin and skin cancer.

9. P soralen P hotochemotherapy Psoralen photosensitizers are activated by UVA radiation. D epth of penetration of PUVA is the mid-dermis. MECHANISM OF ACTION The major photochemical effect is damage to DNA. The changes in DNA differ from those of UVB and UVA without psoralens.

10. Psoralens - T wo double bonds that can absorb UVA radiation. When administered to an individual, these compounds intercalate with DNA. Following UVA exposure, they form a single adduct with DNA and then become a bifunctional adduct, cross-linking the DNA strands in the double helix when a second photon is absorbed. Augments production of ROI such as singlet oxygen. This effect has been implicated in induction of the COX enzyme and activation of arachidonic acid pathways.

11. UVA1 PHOTOTHERAPY 340–400 nm Penetrate more deeply into the skin than UVB or shorter range UVA called UVA2 (i.e., 320–340 nm). MECHANISM OF ACTION Induce T-cell apoptosis- atopic dermatitis and MF Reduction in mast cells and Langerhan cells Increase collagenase expression - morphoea , keloid Tanninng - prophylaxis of PLE.

12. EFFECTS OF PHOTOTHERAPY ON THE IMMUNE SYSTEM P hotoimmunological effects - Efficacy in cutaneous diseases in which T-cell hyperactivity predominates (e.g., psoriasis, atopic dermatitis, lichen planus). Normally, both effector and regulatory T-cells are generated, with the overall intensity of the immune response dependent on the relative proportion of effector and regulatory T-cells populations that are present . UVB inhibits activation of effector T-cells. No effect on formation of regulatory T-cells.

13. Equilibrium of effector and regulatory T-cells is biased towards a diminished cell-mediated immune response. It is because of disruption of the activities of dendritic cells within the skin. This is due to direct effects of UVB on dendritic cells and indirectly through the production of IL-10 and PGE2, which diminish the capacity of dendritic cells to present antigen to effector T-cells and to suppress T-cell responses.

14. Increased levels of IL-10 have been found after UVB, UVA1, and PUVA exposure. UVB radiation of keratinocytes alters expression of surface molecules and induces the synthesis & secretion of immuno modulatory soluble factors, including IL-7, IL-6, IL-8, TNF- α and PGE-2. UVB is an inductive stimulus for c yclooxygenase-2 , which is important for PGE2 production. Increased agonists of the PAF receptor following UVB exposure 1. MSH 2. Calcitonin gene related peptide .

15. PUVA has effects similar to UVB with respect to APCs within the skin, B alance between effector and regulatory T-cells, and Production of soluble immunosuppressive mediators. P hototherapy causes cell death by apoptosis in T-cells present in cutaneous lymphoid infiltrates . This has been demonstrated for UVA1 phototherapy in the lymphocytic infiltrate in atopic dermatitis, and for Narrow band UVB in psoriasis.

16. E ffect on expression of ICAM-1 (CD54) and other adhesion molecules. ICAM-1 can be induced in a variety of inflammatory skin conditions. ICAM-1 facilitates T-cell binding to keratinocytes, through its interaction with LFA-1 that is present on T-cells. UV radiations interfere with keratinocyte expression of ICAM-1, and this contribute to its efficacy in diseases, which have increased keratinocyte ICAM-1 expression.

17. EFFECTS OF PHOTOTHERAPY ON MAST CELLS Both UVA1 and PUVA have deleterious effects on mast cells , although the mechanisms of action differ. PUVA is not cytotoxic for mast cells, so reduction in mast cell concentrations in the dermis of PUVA-treated skin is relatively less. It stabilizes mast cell membranes & limits the release of histamine and other mediators. Chronic therapy with UVA1 results in apoptosis of mast cells with a marked reduction in their concentrations in the dermis .

18. EFFECTS OF PHOTOTHERAPY ON COLLAGEN One of the effects of UVA-induced generation of reactive oxygen intermediates is activation of matrix metalloproteinase-1 (MMP-1 ). Major biologic activity of MMP-1 is degradation of collagen. UVA radiation - ↑ the production of IL-1 and IL-6 which stimulate MMPs. PUVA has also been shown to increase MMPs. Above effects provide rationale for use in sclerotic skin diseases.

19. EFFECTS OF PHOTOTHERAPY ON THE EPIDERMIS UVB, PUVA, and UVA all cause acanthosis of the epidermis and thickening of the stratum corneum . This accentuates light scattering and decreases the equivalent number of photons reaching lower levels of the epidermis and dermis where therapeutic targets lie. Phototherapy treatment doses to be progressively ↑. It is the basis for management of chronic photosensitivity disorders because this “hardens” the skin, permitting patients to tolerate greater amounts of sun exposure.

20. EFFECTS OF PHOTOTHERAPY ON MELANOCYTES Exposure to ultraviolet radiation stimulate melanogenesis , which is a consequence of DNA damage and/or its repair. T reatment of melanocytes with DNA repair enzymes increases the melanin content of melanocytes. Application of small fragments of thymidine dinucleotides to guinea pig skin produces a tanning response. S timulatory effects on melanogenesis ↑ the tolerance of patients with some photosensitivity disorders to ambient sun exposure, but also decrease the efficacy of phototherapy.

21. Narrowband UVB and PUVA used to repopulate vitiliginous skin with melanocytes. M echanism of repigmentation - stimulation of hair follicle melanocyte proliferation and migration. Cytokines and other inflammatory mediators released from keratinocytes stimulate inactive melanocytes in the outer root sheath of follicles to proliferate, mature, and migrate to repopulate the interfollicular epidermis.

22. PUVA may induce repigmentation in vitiligo in following ways : 1 . I ncreasing the number of functional melanocytes. 2. A ugmenting the development and melanization of melanosomes and increasing the transfer of melanosomes to keratinocytes. 3. S timulation of tyrosinase activity. 4 . E nhancing the migration of activated melanocytes from skin appendages. 5 . G enerating a suppressor cell population which suppresses the stimulus for melanocyte destruction during therapy .

23. BASIC PRINCIPLES OF PHOTOTHERAPY DEVICES AND TYPES OF LAMPS Phototherapy devices generate light by the conversion of electrical energy into electromagnetic energy. Filters and fluorophores are used to modify the output such that the desired wavelengths are emitted. Incandescent lamps G enerate UVR by passing an electric current through a thin tungsten filament, which, in turn, generates heat and light. Inefficient light sources. Relatively short life spans .

24. Arc or gas discharge lamps They were the first effective artificial sources of UVR. When a high voltage is passed across two electrodes in the presence of a gas, the electrons of the gas atoms become excited. When the gas electrons return to their ground state, light is emitted. The type of gas incorporated into the lamp determines the wavelengths that are emitted (i.e., spectral output).

25. Fluorescent lamps M ost commonly used sources of therapeutic UV light. C hemicals called phosphors ( a specific type of chromophore) absorb and then reemit light. The light that is reemitted is of lower energy ( & thus longer wavelength) than the inciting light. UVC irradiation (254 nm) generated from a low pressure mercury lamp is converted to the longer UVB and UVA wavelengths of light that are desirable for phototherapy.

26. UV-B PHOTOTHERAPY BB-UVB : Fluorescent lamps are used. Wavelengths < 300 nm are implicated in causing non melanoma skin cancers and inducing erythema. NB-UVB : 308-313 nm wavelength Philips TL-10 lamp with an emission spectrum (311-312 nm). Reduction in erythemogenic wavelengths in the 290-305 nm range. 5-6 fold increased emission of the longer UVB wavelengths. 5-10 fold less potent than BBUVB for erythema induction, hyperplasia, edema and Langerhans cell depletion from the skin. More suppressive effect than BBUVB.

27. INDICATIONS Psoriasis Chronic atopic dermatitis Generalized vitiligo Lichen planus CTCL early stage Seborrhiec dermatitis Photosensitive disorders – PMLE/solar urticaria (HARDENING PROTECTIVE EFFECT) Chronic urticaria Pruritus due to polycythemia vera , liver cirrhosis, renal insufficiency Actinic prurigo Acquired perforating dermatosis

28. MINIMAL ERYTHEMA DOSE Minimal erythema dose (MED) is determined by exposing 6 1cm2 areas on the lower back or inner aspect of the forearm to 200, 400, 600, 800, 1000 , 1200 mJ /cm2 of UVB radiation from the same device that will be used for phototherapy. UVB exposed areas of skin are examined 24 hrs later & the smallest UV dose that results in uniform erythema over the entire area , is MED. Poor correlation between MED and skin type .

29. UVB MED gives an objective measure of a patient’s cutaneous reactivity to UVB . Phototherapy - initiated at 50% - 70% of MED. initial dose based on Fitzpatrick skin phototype . Subsequent exposures – 2-5 times per week Dose is ↑ at each treatment, assuming the patient has not developed an erythema response . If erythema occurs, then, depending on its severity, the dose is either reduced or the treatment is delayed.

30. Narrowband UVB Phototherapy

31. Skin Phototype I Always burn , never tan II Always burn, but sometimes tan III Sometimes burn ,always tan IV Never burn , always tan V Moderately pigmented VI Blacks * Patients with erythrodermic psoriasis are to be classified as skin phototype I

32. SAFE LIMIT N o established safe limit for its maximum safe duration. Njoo et al - responsive patients can be given t/t for a max. of 24 months. After 1 year, resting period of 3 months is advised to minimize cumulative dose. In children, the max. duration allowed is 12 months . Subsequently, if required, only limited areas should be exposed . If no response is observed after six months, further therapy should be discouraged.

33. SIDE EFFECTS

34. UVA-1 PHOTOTHERAPY UVA-1 (340-400nm) 1981 – 1 st report describing a device capable of emitting UVA1. 1992---therapeutic benefit of UVA1 was demonstrated for atopic dermatitis. Longer wavelength allows greater penetration into the skin than UVB or UVA-2(320-340nm). Initial problems with UVA-1 devices---intense heat generation. Newer devices---filtering and cooling systems which filter out all wavelengths above 530nm. Flourescent lamps – low and medium dose Metal halide - high dose

35. Uses - Atopic dermatis (acute flares) CTCL Sclerosing skin disease Morphea Systemic sclerosis lichen sclerosus GVHD Pseudoscleroderma Cutaneous mastocytosis PLC and PLEVA SLE Dyshidrosis Chronic hand eczema Granuloma annulare Eosinophilic fasciitis

36. Side effects - Acute – Erythema Tanning PMLE Itching Chronic – As UVA1 has only been available since 1990s, the long term effects on carcinogenesis are under investigations.

37. PHOTOCHEMOTHERAPY Psoralen-UVA photochemotherapy combines the oral ingestion or topical application of psoralens with exposure to UVR in the UVA range. Three forms of psoralen are used in photochemotherapy regimens: 8-methoxypsoralen (8-MOP ) 5-methoxypsoralen (5-MOP ) 4,5 ′, 8-trimethylpsoralen (TMP)

38. PSORALENS -- phototoxic compounds that enter cells and then absorb photons to produce photochemical reactions that alter the function of cellular constituents No therapeutic effect on it’s own but with UVA radiation. Both natural and synthetic belonging to tricyclic furocoumarins . Natural psoralen present in fruits & vegetables like lime, lemons, & figs.

39. Methoxsalen or 8-MOP obtained from the seeds of a plant called Ammi majus . It is most widely used and the only psoralen available in the United States. Bergapten or 5-MOP and trioxsalen (TMP) or 4, 5', 8 trimethylpsoralen are available in Europe and elsewhere.

40. There are two oral formulations of 8-MOP: M icronized form - Dose of 0.6 mg/kg 120 minutes prior to UVA exposure . 2. Dissolved form - Dose of 0.4–0.6 mg/kg 90 minutes before UVA exposure. The dissolved preparation – Faster absorption Higher serum levels. Therefore, more commonly employed as a part of PUVA phototherapy regimens.

41. PHARMACOKINECTICS OF PSORALENS Lipophilic , non ionized , poorly soluble in water Large inter individual variation in absorption Physical formulation influence absorption Food especially fat decrease absorption ( ideally should be taken fasting ) Saturable 1 st pass metabolism via liver Serum half life – 1 hr Phototoxic - 8 MOP > 5 MOP >TMP Metabolized in liver - rapid and complete CYP450 inducing drugs accelerate its metabolism 70% renal excretion, complete in 12 hrs.

42. NEWER PSORALENS 6 Methyl anillin & 7 methyl pyridopsoralen Strong antiproliferative action Lack phototoxic Less carcinogenic & mutagenic 3 Carbethoxypsoralen As effective as 8 MOP Less phototoxic Non carcinogenic (in mice)

43. Photosensitivity effects of photochemotherapy PUVA erythema does not appear before 24 to 36 hours and peaks at 72 to 96 hours , or even later. UVB erythema that appears after 4 to 6 hours and peaks 12 to 24 hours after exposure. Severe PUVA reactions may lead to blistering and to superficial skin necrosis. Overdoses of UVA are frequently followed by swelling, intense pruritus , and, sometimes, by a stinging sensation in the affected skin area, possibly as a consequence of damage of superficial nerve endings

44. Pigmentation is the 2 nd important effect of PUVA. I t may develop without clinically evident erythema, especially when oral 5-MOP or TMP is used. In unaffected skin, PUVA pigmentation is maximal approx. 7 days after a PUVA exposure & may last from several weeks to months----VITILIGO As with sun-induced pigmentation, the individual's ability to tan is genetically determined, but the dose-response curve is much steeper. A few PUVA exposures result in a much deeper tan than that produced by multiple exposures to solar radiation.

45. INDICATIONS OF PUVA FDA APPROVED Psoriasis Vitiligo Increasing tolerence to sunlight/enhancing pigmentation OFF LABEL DERMATOLOGICAL USES NEOPLASTIC Mycosis fungoides Histiocytosis X PAPULOSQUAMOUS /DERMATITIS Atopic dermatitis Seborrheic dermatitis Chronic hand dermatitis Palmoplanter pustulosis lichen planus Pityriasis lichenoides lymphomatoid papulosis PHOTOSENSITIVITY DERMATOSIS (also used for prevention) PMLE Erythropoietic protoporphyria Solar urticaria Chronic actinic dermatitis

46. OTHER PRURITIC DERMATOSIS - Dermatographism - Aquagenic urticaria / pruritis -Chronic urticaria - Urticaria pigmentosa -Polycythemia vera -Idiopathic pruritis - Prurigo nodularis OTHER IMMUNOLOGICAL CONDITION -Alopecia areata -Graft vs. host reaction - Morphea -Linear scleroderma

47. MINIMUM PHOTOTOXIC DOSE MPD is determined by giving the patient dose of the oral psoralen to be used for the photochemotherapy treatment and exposing 6 one-cm2 areas of skin to gradually increasing doses of UVA . The MPD is evaluated 72 hours after UVA exposure and is the lowest amount of UVA that produces a uniform erythema over the entire area. Treatments are usually given 2–4 times per week, avoiding consecutive days.

48. SIDE EFFECTS Gastrointestinal disturbance CNS symptoms-headache, dizziness Bronchoconstriction Toxic hepatitis Drug fever, Exanthem Erythema Pruritus Subacute phototoxicity Photoonycholysis Friction blister Phytophotodermatitis Koebner phenomenon PMLE Lupus erythematosus Guttate psoriasis Seborreic dermatitis Herpes simplex

49. LONG TERM SIDE EFFECTS

50. CARCINOGENESIS The risk of SCC, but not of BCC, is significantly increased. Increased risk for melanoma – an area of controversy Dose dependent More in skin type I/I High risk –past family history of skin malignancy or dysplastic nevi, or on cyclosporin , Mtx , UVB therapy Mutation in p53 & p16 Defect in DNA repair mechanism Free radical damage

51. CONTRAINDICATIONS ABSOLUTE SLE with photosensitivity Xeroderma pigmentosum Lactation History of idiosyncratic reaction to psoralen Pemphigus and pemphigoid

52. RELATIVE CONTRAINDIACTIONS Photosensitivity or photosensitizing drugs Prior exposure to ionizing rays or arsenic H /o skin cancer or photo damage Pregnancy Severe cardiac ,renal, hepatic disease Young age (<12 yrs .) SAFE LIMIT – Limit total no . of life time PUVA sessions per patient to < 150-200.

53. TOPICAL PUVA 8-MOP/TMP – cream, lotion, ointments TMP – more phototoxic (30 times) but weaker penetration. Preferred to oral PUVA in conditions : In patients with hepatic/renal dysfunction/GI disturbances In patients with cataract In claustrophobic individuals & to permit shorter irradiation time Psoralen drugs interaction Disease limited to palms and soles

54. INDICATIONS OF TOPICAL PUVA Palmoplantar pustulosis Hyperkeratotic eczema Atopic eczema Lichen planus Systemic sclerosis/ morphea Mycosis fungoides & sezary syndrome Parapsoriasis PMLE Vitiligo Aquagenic urticaria / uraemic pruritis

55. ADVERSE EFFECTS OF TOPICAL PUVA Non- uniform distribution on skin. Time- consuming. Does not prevent the development of new active lesions in previous unaffected, untreated areas. Unpredictably higher phototoxicity , blistering and cosmetically uneven pigmentation . Pruritis – equally common with oral & bath PUVA. Ocular toxicity – not reported but paint PUVA which reaches higher plasma conc. may be responsible.

56. Advantages of Bathwater psoralen phototherapy is – Provides a uniform drug distribution over the skin surface Associated with very low psoralen plasma levels Rapid elimination of free psoralens from the skin Circumvents gastrointestinal side effects and possible phototoxic hazards to the eyes associated with the oral form. Skin psoralen levels are highly reproducible , and photosensitivity lasts no more than two hours.

57. Modification of Phototherapy Dose for Erythema: No erythema Increase by 25% Erythema with no pain No increase Erythema with pain Hold treatment until symptoms subside Erythema with pain and blistering Hold treatment until symptoms subside and reduce dose by 50% from last dose

58. < 1 week No increase in dose 1-2 weeks Decrease dose by 50% (BB-UVB) or 25% (NB UVB or PUVA) 2-3 WEEKS Decrease dose by 75% (BB-UVB) or 50% (NB UVB or PUVA) >3 WEEKS Restart at initial exposure dose Modification of Phototherapy Dose for missed treatments:

59. PHOTOTHERAPY IN CHILDHOOD O ral PUVA is restricted < 12 yrs . Majority of the phototherapy experts do not recommend UVA1 in subjects < 18 yrs. of age. If used, it should not be > 2 cycles yearly., with no > 15 irradiation exposures per cycle. NB UVB remains the safest. U se of phototherapy in the pediatric population has remained limited and studies are lacking about long-term risk of in children.

60. NEWER FORMS OF PHOTOHERAPY

61. EXTRACORPOREAL PHOTOCHEMOTHERAPY Introduced in early 1980s for palliative treatment of CTCL. Immunomodulatory therapy that combines leukapheresis with phototherapy. Treat autoreactive or neoplastic disorders caused by aberrant clones of T lymphocytes.

62. Patient’s blood is extracted and centrifuged to obtain the leukocyte concentrate. 8-MOP is administered directly into the bag containing the leukocyte concentrate. The 8-MOP molecule enters the cell and its nucleus quickly. Exposed to UV-A radiation (1-2 J/cm2)

63. T-Cell Apoptosis. Dendritic cells - B lood monocytes adhere to the plastic surface of the device, get converted to immature dendritic cells. Anti tumor response – CD 8 cells. S timulate the Th1 response.

64. INDICATIONS OF ECP FDA APPROVED – CTCL Other dermatologic uses CONNECTIVE TISSUE DISEASE Scleroderma Lupus erythematosus BULLOUS DERMATOSIS Pemphigus vulgaris Pemphigus foliaceous EBA GRAFT- VERSUS HOST DISEASE Acute and chronic GVHD Prevention of GVHD OTHER DERMATOSES Nephrogenic fibrosing dermatopathy Solar urticaria Oral erosive LP

65. PHOTODYANAMIC THERAPY Photodynamic therapy (PDT) aims to destroy the desired target selectively, thereby minimizing damage to normal tissue. The photodynamic reaction consists of the excitation of photosensitizers (usually porphyrins) by visible light in the presence of oxygen, resulting in the generation of ROI, particularly singlet oxygen. These reactive oxygen species mediate cellular and vascular effects.

66. Kennedy, et al. in 1990. Destroy the desired target selectively. 5-aminolaevulinic acid is the main agent used. Actinic keratoses of the face and scalp . Bowens disease. Superficial basal cell carcinomas. Acne.

67. Acne vulgaris Porphyrins accumulated in the bacteria Propionibacterium acnes one of the etiologic factors involved in the pathogenesis, allows phototherapy to be a successful modality. Although blue light is best for the activation of porphyrins, red light is best for deeper penetration and an anti-inflammatory effect. RATIONALE OF PHOTOTHERAPY - Porphyrins produced by P. acne Photothermal damage to the sebaceous glands Anti-inflammatory effect

68. Photodynamic therapy in acne Aminolevulinic acid (ALA) - taken up by the pilosebaceous units. Destruction of pilosebaceous units & killing of P. acnes.

69. TARGETED PHOTOTHERAPY Targeted phototherapy delivers therapeutic doses of UVR only to lesional skin. A lso known as focused phototherapy, concentrated phototherapy , and microphototherapy .

70. ADVANTAGES Exposure of involved areas only ,thus minimizing side effects of unaffected skin. Shortened duration of session. Higher doses can be delivered selectively to the lesions, thereby enhancing efficacy. Shorten duration of treatment. Allows treatment of difficult areas such as scalp, nose, genitals, oral mucosa, ear, etc. Easy administration for children. Occupy less space.

71. L imitations of targeted phototherapy are : Expensive device N ot practical for patients with more than 10% to 20% of BSA involved . P reventive action of phototherapy on uninvolved but at-risk skin is also lost. Targeted phototherapy devices include : E xcimer lasers. Non laser devices known as Monochromatic Excimer L ight (MEL ) devices.

72. Both devices have been used to deliver targeted therapy to treat specific lesions of diseases such as psoriasis and vitiligo. Both devices deliver monochromatic UVB irradiation (most commonly at 308 nm ). Lasers - D eliver UVR to a smaller area but are capable of emitting higher amounts of radiation over a shorter period of time. MEL devices - Deliver monochromatic irradiation to a larger area but with a lower power density. There are also several devices that emit polychromatic UVA or UVB radiations.

73. SKIN CONDITIONS AMENABLE TO TARGETED PHOTOTHERAPY Psoriasis Vitiligo Oral LP Alopecia aerata Atopic dermatitis Mycosis fungoides Lymphmatoid papulosis Hypopigmented scars/ striae