PHOTOTHERAPY BEYOND PSORIASIS AND VITILIGO

DR. MIKHIN GEORGE THOMAS

• Definition • History• Types of phototherapy

• Mechanism of action• Schedules and protocols• Combination therapy

• Acute and long term effects of

phototherapy• Indications of phototherapy• Newer forms of phototherapy• Extracorpreal photopheresis• Targeted phototherapy

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

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

• Revival of phototherapy- Ammi Majus and Bergapten

• PUVA –Fitzpatrick• 1992- UVA1 for atopic dermatitis• 1980s- ECP introduced for CTCL

TYPES OF PHOTOTHERAPY

Ultraviolet A Ultraviolet B Targeted phototherapy

NEWER FORMS OF PHOTOTHERAPY

• Excimer laser• Intense pulse light therapy• Light-based targeted phototherapy• Photodynamic therapy• Balneotherapy

MECHANISM OF ACTION

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.

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.

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.

Induces reactive oxygen species formation-cell membrane and mitochondrial membrane damage and eventual death of antigen-presenting cells

Stabilizes the mast cells Upregulates MMP

PSORALENS

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

FACTORS

INSOLUBLE IN WATER FOOD HINDERS ABSORPTION FIRST PASS METABOLISM ABSORPTION DEPENDS ON THE PHYSICAL

PROPERTIES LARGE INTERINDIVIDUAL VARIATION IN

ABSORPTION

JAAD 2010

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

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

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

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

UV- B

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

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

Ongoing monitoring: Regular full skin examination to monitor signs of photoaging, pigmentation, and cutaneous malignancies

Pregnancy: Generally considered safe (expert opinion)

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

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

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

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

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

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

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

FDA APPROVED INDICATIONS

PSORIASIS VITILIGO

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

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

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.

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

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

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

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

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

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

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

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

URTICARIA PIGMENTOSA

TEMPORARY INVOLUTION Loss of Darier’s sign Relief of itching Flattening Complete disappearance of cutaneous

macules and papules

Histamine induced migraines and flushing also subsides with continued treatment

Gradually increasing doses to be administered to avoid degranulation of mast cells

PITYRIASIS LICHENOIDES

PUVA found to be beneficial NB UVB widely used though the

condition tends to remain persistent in some cases.

Conflicting reports

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

PITYRIASIS RUBRA PILARIS

Some respond, others flare Some require combination with

retinoids or methotrexate

GRANULOMA ANNULARE

• Lesions found to resolve completely

• Relapse frequent• Long term maintenance required

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

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

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

MECHANISM

Induction of interstitial collagenase (matrix metalloproteinase 1)

Release of singlet oxygen Release of signaling peptides such a

interleukin- 1a (IL-a), IL-1b, and IL-6 Release of hydrogen peroxide, which increases

mRNA levels of interstitial collagenase

Different types of phototherapy have been used

UV-A 1 found to be most effective Longer the wavelength greater the

penetration

PRURITUS

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

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

REGULAR SUN EXPOSURES REQUIRED FOR MAINTENANCE

REMISSION FOR 2-3 MONTHS

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

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)

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

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

ADVERSE EFFECTS Headache Nausea Fever Muscle pain Hypotension Exacerbation of skin lesions after

treatment Vasovagal syncope Septicemia Injection site infection.

TARGETED THERAPY

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

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

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.

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

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

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

ULTRAVIOLET A1 THERAPY

o 340-400nmo Used as a tool for provocative testing

for PMLEo Photopatch testingo Treatment of several ultraviolet

responsive conditions

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.

INDICATIONS

Atopic dermatitis PLE Morphoea

CTCL Follicular mucinosis Hand eczema Hypereosinophilic syndrome GVHD POEMS Keloids

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

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

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

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

Porphyrins produced by P. acne Photothermal damage to the sebaceous

glands Anti-inflammatory effect

PHOTODYNAMIC THERAPY IN ACNE

Aminolevulinic acid (ALA)- taken up by the pilosebaceous units

Destruction of pilosebaceous units and killing of P.acne

ADVERSE EFFECTS

Discomfort Transient hyperpigmentation Exfoliative erythema Crust formation Photosensitivity

TO SUM UP…….

Good modality of treatment Alternative mode of management Relapse is common Carcinogen Cost of treatments