Phototherapy beyond psoriasis and vitiligo

phototherapy in dermatology, other than psorasis and vitiligo.

1. PHOTOTHERAPY BEYOND PSORIASIS AND VITILIGO DR. MIKHIN GEORGE THOMAS

2. Definition History Types of phototherapy Mechanism of action Schedules and protocols Combination therapy

3. Acute and long term effects of phototherapy Indications of phototherapy Newer forms of phototherapy Extracorpreal photopheresis Targeted phototherapy

4. phototherapy Phototherapy is the use of ultraviolet radiation or visible light for therapeutic purposes UVB radiation (290–320 nm) is absorbed by the epidermis and superficial dermis UVA radiation (320–400 nm) can reach the mid- or lower dermis

5. Heliotherapy Atharva veda - Psoralia Corylifolia 1896-Niels Ryberg Finsen 1923-Wiliam Henry Goeckerman 1953- John Ingram

6. Revival of phototherapy- Ammi Majus and Bergapten PUVA –Fitzpatrick 1992- UVA1 for atopic dermatitis 1980s- ECP introduced for CTCL

7. Types of phototherapy Ultraviolet A Ultraviolet B Targeted phototherapy

8. Newer forms of phototherapy Excimer laser Intense pulse light therapy Light-based targeted phototherapy Photodynamic therapy Balneotherapy

9. Mechanism of action

10. UV-B Interferes with the synthesis of proteins and nucleic acids-decreased proliferation of epidermal keratinocytes . Early changes Formation of pyrimidine dimers Membrane lipid peroxidation Induction of transcriptional factors.

11. Delayed changes Alteration of antigen presenting cells and cellular signaling mechanisms- Î IL10,PGE2 Decrease the number of Langerhans cells thus inhibiting the ability of dendritic cells to present antigens .

12. PUVA Similar to UVB irradiation Penetrates into the dermis Effects on dermal dendritic cells, fibroblasts, endothelial cells, and mast cells as well as skin infiltrating inflammatory cells including granulocytes and T lymphocytes .

13. Induces reactive oxygen species formation-cell membrane and mitochondrial membrane damage and eventual death of antigen-presenting cells Stabilizes the mast cells Upregulates MMP

14. psoralens Naturally occurring compounds 8-methoxypsoralen (8-MOP) 5-methoxypsoralen (5-MOP) 4,5′,8-trimethylpsoralen(TMP)

15. factors INSOLUBLE IN WATER FOOD HINDERS ABSORPTION FIRST PASS METABOLISM ABSORPTION DEPENDS ON THE PHYSICAL PROPERTIES LARGE INTERINDIVIDUAL VARIATION IN ABSORPTION

16. JAAD 2010

17. 8-Methoxypsoralen, 0.4-0.6 mg/kg, taken 1-2 h before exposure to UVA UV protective eye wear should be worn when outdoors for 12 h post ingestion Treatment -2-3/wk Initial improvement frequently seen within 1 mo of therapy

18. Combination UVB with topical therapies Emollients increase the transmission of UV radiation by altering the optical properties of psoriatic skin lesions and improving therapeutic efficacy Sunscreens

19. No added benefit with concomitant topical steroid use Calcipotriol use has shown equal efficacy with twice weekly NBUVB when compared to thrice weekly monotherapy With topical retinoids , better efficacy but NBUVB dosage to be reduced to avoid burning of skin

20. Combination of methotrexate along with phototherapy reduces the dose related toxicity Combination with cyclosporine not tried much as monotherapy itself has high chance of non melanoma skin cancers Other combinations include retinoids and biologics

21. UV- B

22. Contraindications : Lupus erythematosus or Xeroderma Pigmentosum Caution should be exercised in : Patients with skin types I and II History of arsenic intake or previous treatment with ionizing radiation therapy, History of melanoma or multiple nonmelanoma skin cancers Any medical condition that is severe enough that patient cannot tolerate heat or prolonged standing in light box

23. Drug interactions: Cautious use with other photosensitizing medications When used in conjunction with systemic retinoids , dose of both retinoids and UVB may need to be lowered Baseline monitoring: Full body skin check before initiation of therapy

24. Ongoing monitoring: Regular full skin examination to monitor signs of photoaging , pigmentation, and cutaneous malignancies Pregnancy: Generally considered safe (expert opinion)

25. Nursing: Generally considered safe (expert opinion) Pediatric use: No adequate study; may be used with caution in individuals aged\18 y Psoriatic arthritis: No studies

26. Toxicity: PUVA Acute: Nausea and vomiting are common Dizziness and headache are rare Erythema : peaks at 48-96 h Pruritus Tanning: starts 1 wk after PUVA Blisters Photo- onycholysis Melanonychia

27. Chronic: Photocarcinogenesis (SCC, BCC, and possible melanoma) Increased risk of photocarcinogenesis in Caucasians with skin types I-III after 200 treatments; this risk not present for non-Caucasians Photoaging and lentigines are common, especially in patients of skin types I-III and are cumulative UVA dose dependent

28. Contraindications: Known Lupus Erythematosus , Porphyria, or Xeroderma Pigmentosum Caution should be exercised: In patients with skin types I and II who tend to burn easily History of arsenic intake or previous treatment with ionizing radiation therapy History of melanoma or multiple non melanoma skin cancers

29. Any medical condition that is severe enough that patient cannot tolerate heat or prolonged standing in light box Severe liver disease that could lead to toxic levels of psoralens , possibly those who have been treated with cyclosporine or Methotrexate pregnant or nursing

30. Caution when patient is taking other photosensitizing medication Should decrease UVA dose by one-third if oral retinoids are started while patient is receiving PUVA Skin cancer screening Eye examination ANA panels (anti-Ro/La antibodies) Liver enzymes

31. Regular full skin examination because of potential increased risk of photocarcinogenesis in Caucasians In patients who are noncompliant with eye protection, yearly eye examination Pregnancy: Category C Nursing: Contraindicated for period of 24 h after ingesting psoralen Pediatric use: No studies; may be used with caution in individuals aged\18 y Psoriatic arthritis: No studies

32. FDA approved indications PSORIASIS VITILIGO

33. OFF LABEL INDICATIONS Malignancy Mycosis fungoides Inflammatory Seborrheic dermatitis Photodermatoses Actinic reticuloid PMLE Solar urticaria Clonal disorders Parapsoriasis Pityriasis lichenoides Immune dysfunction Atopic dermatitis Alopecia areata Lichen planus Others Granuloma annulare Urticaria pigmentosa Lichen myxedematous Morphoea

34. Mycosis fungoides (MF): Non-Hodgkin Lymphomas (NHL), which are characterized by their initial presentation in the skin MF (together with other types of CTCL) is the only malignant disease that is treated with ultraviolet (UV) radiation, the major environmental skin carcinogen UVB decreases the allo -activating and antigen presenting capacity of Langerhan cells

35. Treatment schedule consists of clearance, maintenance and follow up Histological evaluation of clearing of lesions Maintenance therapy includes two therapies a week for 1month and then one exposure for a month for 3-6months.

36. PUVA has been tried in all stages of mycosis fungoides Most successful in early-stage disease, i.e. less than stage IIa . Rate of complete remission after an initial course of PUVA- 90% for stage IA, 76% for stage IB, 78% for stage IIA, 59% for stage IIB, and 61% for stage III disease

37. Once a patient achieves complete remission, a confirmatory biopsy of a previously exposed site is often recommended Bath PUVA has been utilized as a therapeutic modality in patients in whom oral psoralens cannot be given There were no differences in time to relapse between patients treated with PUVA and those treated with narrow-band UVB

38. reasonable approach Start with NB-UVB and in case of lack of response switch to PUVA Patches and thin plaques-NB-UVB In late stage disease-PUVA may be combined with methotrexate , bexarotene or interferon as first-line therapy

39. Complete clearing may be induced when the cells are confined to the epidermis and the superficial dermis and do not exceed the depth of UVA penetration into the skin. PUVA is not sufficient as monotherapy Reduce the tumor burden in the skin Improve the quality of life for patients

40. ATOPIC DERMATITIS Second‑line treatment in the management of atopic dermatitis Moderate, severe and erythrodermic cases respond to PUVA More difficult to treat Alteration of lymphocyte function in the dermal infiltrate. Airconditioned treatment cabinets improve patients tolerance to phototherapy

41. The action of UVA‑1 is mediated through T lymphocyte apoptosis and decreased expression of interferon γ ( IFN‑γ ) by activated T cells. Medium dose UVA1 and NB-UVB phototherapy are most effective as observed in various randomized controlled trials and half‑body paired comparison studies RELAPSE IS FREQUENT NEED PROLONGED TREATMENT COMBINATION WITH STEROIDS

42. LICHEN PLANuS Effective alternative to steroids in disseminated lesions, recalcitrant oral lesions Response rate – 50 to 90% More sessions Post inflammatory hyperpigmentation More cumulative doses required Re-PUVA a better option

43. GRAFT VS HOST DISEASE Acute GVHD shows good response Lichenoid forms respond better Localized and circumscribed GVHD respond Widespread sclerodermoid forms respond poorly Increments are done very slowly

44. URTICARIA PIGMENTOSA TEMPORARY INVOLUTION Loss of Darier’s sign Relief of itching Flattening Complete disappearance of cutaneous macules and papules

45. Histamine induced migraines and flushing also subsides with continued treatment Gradually increasing doses to be administered to avoid degranulation of mast cells

46. pityriasis lichenoides PUVA found to be beneficial NB UVB widely used though the condition tends to remain persistent in some cases. Conflicting reports

47. parapsoriasis Phototherapy is indicated for all types of parapsoriasis and its clinical variants. Clearing of recalcitrant lesions as well as preventing evolution in to MF

48. PITYRIASIS RUBRA PILARIS Some respond, others flare Some require combination with retinoids or methotrexate

49. GRANULOMA ANNULARE Lesions found to resolve completely Relapse frequent Long term maintenance required

50. Lichen myxoedematosus Papular lichenoid eruption and mucin deposition in the dermis Paraproteinemia Histologically , the proliferation of fibroblasts is enhanced in the dermis, and collagen bundles are split by mucinous infiltration PUVA treatment has a suppressive effect on DNA synthesis and cell proliferation

51. ALOPECIA AREATA Found to respond after a number of sessions Cirscumscribed lesions respond better compared to total alopcia Follow up studies showed phototherapy not very effective Relapse is high

52. MORPHEA Low dose ultraviolet A-1 phototherapy (UVA-1, 340–400 nm) has been shown to improve symptoms of morphea Induce a marked softening of the skin Complete resolution of the thickened and hyalinized collagen bundles Return to histologic features of normal skin

53. mechanism Induction of interstitial collagenase (matrix metalloproteinase 1) Release of singlet oxygen Release of signaling peptides such a interleukin- 1 a (IL-a), IL-1b, and IL-6 Release of hydrogen peroxide, which increases mRNA levels of interstitial collagenase

54. Different types of phototherapy have been used UV-A 1 found to be most effective Longer the wavelength greater the penetration

55. pruritus Renal Hepatic Aquagenic pruritus Aquagenic urticaria Chronic urticaria Hiv and eosinophilic folliculitis

56. PHOTODERMATOSES Preventive treatment by producing hardening 3-4 weeks of PUVA sufficient to suppress the disease PUVA induces pigmentation rapidly 10% report new lesions- no need to reduce dosing 5- MOP preferred

57. REGULAR SUN EXPOSURES REQUIRED FOR MAINTENANCE REMISSION FOR 2-3 MONTHS

58. 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

59. 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)

60. T-Cell Apoptosis Dendritic cells- blood monocytes adhere to the plastic surface of the device, get converted to immature dendritic cells Anti tumor response –CD 8 cells stimulate the TH1 response

61. Predictors of good response Erythroderma Less than 2 years since diagnosis Leukocyte count lower than 20,000/ μL Presence of 10% to 20% circulating Sézary cells Absence of palpable lymph nodes Absence of visceral involvement Absence of previous intensive chemotherapy High peripheral blood CD8 lymphocyte count

62. Adverse effects Headache Nausea Fever Muscle pain Hypotension Exacerbation of skin lesions after treatment Vasovagal syncope Septicemia Injection site infection.

63. TARGETED THERAPY

64. advantages Exposure of involved areas only and sparing of uninvolved areas Quick delivery of energy and thereby shortened duration of treatment Delivery of higher doses (super- erythemogenic doses) of energy because uninvolved areas are not exposed

65. This has been claimed to shorten duration of treatment, leading to less frequent visits to clinic, and thereby lessen the inconvenience for the patient The maneuverable hand piece allows treatment of difficult areas such as scalp, nose, genitals, oral mucosa, ear, etc. Easy administration for children as delivery is hand-held Targeted phototherapy machines occupy less space

66. EXCIMER LASER Mixture of noble gas and a halogen “Excited dimmers.” Depth of penetration is shallow-very precise action Ablative photodecomposition Pulsed wave lasers-they deliver a high energy in a short time, rapidly breaking chemical bonds .

67. Overall treatment time is usually shorter Mean number of treatments and the cumulative UV dose are significantly lower Lower therapeutic cumulative dose of the XeCl laser involves a lower risk of carcinogenesis. This treatment option makes it possible to selectively treat skin lesions and spares uninvolved skin

68. balneotherapy Bath water delivery of 8-methoxypsoralen (bath PUVA) or different salt solutions with a subsequent UVB- or UVA-irradiation Bath PUVA has the advantage of selective and shorter photosensitization no serious side effects Found to be efficacious compared to NBUVB monotherapy

69. Photodynamic therapy 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

70. ULTRAVIOLET A1 THERAPY 340-400nm Used as a tool for provocative testing for PMLE Photopatch testing Treatment of several ultraviolet responsive conditions

71. mechanism Induce T-cell apoptosis- atopic dermatitis and MF Reduction in mast cells and Langerhan cells Increase collagenase expression- morphoea , keloid Tanninng - prophlaxis of PLE.

72. indications Atopic dermatitis PLE Morphoea

73. CTCL Follicular mucinosis Hand eczema Hypereosinophilic syndrome GVHD POEMS Keloids

74. Hand eczema Both local NB-UVB phototherapy and PUVA irradiation show similar beneficial responses. Thick lesions UV-A preferred Studies show UV-A is better, more penetration NB UV-B preferred in dry and dyshidrotic types

75. Seborrheic dermatitis Many patients improve upon exposure to natural sunlight Abnormal immunological response to the yeast or its degradation products may play an important pathogenetic role

76. Modulatory effect on inflammatory and immunological processes in the skin A direct effect of UV irradiation on P. Ovale leading to ultrastructural changes and growth inhibition Long standing cases and widespread involvement responded better Relapse is common

77. 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

78. rationale Porphyrins produced by P. acne Photothermal damage to the sebaceous glands Anti-inflammatory effect

79. photodynamic therapy in acne Aminolevulinic acid (ALA)- taken up by the pilosebaceous units Destruction of pilosebaceous units and killing of P.acne

80. Adverse effects Discomfort Transient hyperpigmentation Exfoliative erythema Crust formation Photosensitivity

81. To sum up……. Good modality of treatment Alternative mode of management Relapse is common Carcinogen Cost of treatments