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 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
 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
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
 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

 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
 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  Immune dysfunction

 Inflammatory • Atopic dermatitis
• Seborrheic dermatitis
• Alopecia areata
 Photodermatoses
• Lichen planus
• Actinic reticuloid
 Others
• PMLE
• Granuloma annulare
• Solar urticaria
• Urticaria pigmentosa
 Clonal disorders

• Parapsoriasis • Lichen myxedematous

• Pityriasis lichenoides • 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

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
URTICARIA PIGMENTOSA
 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
 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
 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
 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
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
ULTRAVIOLET A1 THERAPY

o 340-400nm

o Used as a tool for provocative testing for

PMLE

o Photopatch testing

o 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