Topical photochemotherapeutics

Definition and Scope

Topical photochemotherapeutics refer to a specialized class of dermatologic agents applied to the skin and activated by exposure to specific wavelengths of light, typically ultraviolet A (UVA). The therapeutic mechanism relies on the interaction between the photosensitizing drug and light energy, producing cytotoxic, immunomodulatory, or antiproliferative effects. These agents are most commonly employed in a treatment modality known as topical PUVA therapy (Psoralen + UVA).

This class is primarily used in the management of severe dermatological diseases, particularly those involving keratinocyte proliferation, T-cell dysregulation, or pigmentation disorders.

---

Mechanism of Action

Topical photochemotherapeutics act by:

1. Application of a photosensitizing agent (most commonly a psoralen derivative such as methoxsalen)

2. Irradiation with UVA light (320–400 nm) after a defined latency period

3. Activation leads to:

   • Formation of DNA crosslinks (monoadducts and diadducts) in rapidly dividing keratinocytes

   • Generation of reactive oxygen species (ROS)

   • Apoptosis of T-cells and hyperproliferative epidermal cells

   • Suppression of abnormal immune responses

The therapeutic effects include anti-proliferative, immunosuppressive, anti-inflammatory, and pigment-altering outcomes depending on disease context.

---

Therapeutic Indications

Topical photochemotherapy is used in the management of:

• Psoriasis vulgaris (plaque-type) – particularly localized, recalcitrant plaques

• Vitiligo – re-pigmentation via stimulation of melanocyte proliferation and migration

• Cutaneous T-cell lymphoma (early stages of mycosis fungoides)

• Atopic dermatitis – chronic lichenified lesions

• Lichen planus – refractory skin lesions

• Alopecia areata (investigational use)

• Palmoplantar pustulosis

• Morphea and other localized sclerosing dermatoses

• Chronic hand eczema

Topical PUVA is often reserved for localized, treatment-resistant lesions when systemic therapy is unnecessary or contraindicated.

---

Generic Photosensitizing Agents Used Topically

The primary class of topical photochemotherapeutics is psoralens, which are naturally occurring or synthetic furocoumarins.

1. Methoxsalen (8-MOP, 8-methoxypsoralen)

   • Most widely used psoralen for topical PUVA

   • Derived from Ammi majus plant

   • Lipophilic; readily penetrates the stratum corneum

2. Trioxsalen (4,5′,8-trimethylpsoralen, TMP)

   • Less commonly used topically

   • Also used orally for systemic PUVA

3. Bergapten (5-MOP, 5-methoxypsoralen)

   • Plant-derived; sometimes used in compounded formulations

   • Weaker than methoxsalen

4. Isopsoralen (Angelicin) (experimental use)

   • Less phototoxic; may offer improved safety profile

These agents are typically formulated in alcoholic or emollient bases and applied under occlusion to enhance penetration.

---

Formulations and Preparations

• Methoxsalen 0.1% to 1% solution or gel

• Methoxsalen cream formulations (in ethanol or acetone base)

• Compounded bergapten solutions

• Psoralen-impregnated bathwater (bath PUVA, used in some European centers)

Formulation selection depends on:

• Site of application (thicker or thinner skin)

• Extent of disease

• Risk of systemic absorption

---

Administration Protocol: Topical PUVA

1. Topical Application

   • Applied uniformly to affected area

   • Typically 10–30 minutes before UVA exposure

   • Avoid surrounding healthy skin if possible

2. UVA Irradiation

   • Performed in a controlled phototherapy unit

   • Initial dose determined by Minimal Phototoxic Dose (MPD)

   • Gradual dose increments to minimize burns

3. Frequency

   • 2–4 times per week depending on indication

   • Typical treatment course: 6–12 weeks

4. Post-Treatment Care

   • Avoid sunlight exposure for 24–48 hours to prevent burns

   • Emollients may be used to manage dryness

---

Onset and Duration of Action

• Vitiligo: Repigmentation visible after 2–3 months

• Psoriasis: Clearance typically within 4–6 weeks

• Cutaneous lymphoma: Clinical remission over multiple sessions

---

Adverse Effects

1. Local Effects

   • Erythema, burning

   • Itching

   • Hyperpigmentation

   • Dryness or peeling

   • Blistering if overexposed

2. Long-Term Effects

   • Photoaging (accelerated skin aging)

   • Freckling and lentigines

   • Skin cancer risk (particularly with repeated courses or high doses)

     • Includes squamous cell carcinoma and, rarely, melanoma

     • Lower than with oral PUVA

3. Systemic Absorption (minimal but possible)

   • Potential nausea, headache (rare with topical use)

---

Contraindications

• Photosensitive disorders:

  • Lupus erythematosus

  • Porphyria

  • Xeroderma pigmentosum

• Recent or ongoing radiation therapy

• Active skin infections

• Skin cancer or pre-malignant lesions

• Known allergy to psoralens

• Pregnancy and lactation (relative contraindication)

---

Precautions

• Use eye protection during and for 24 hours post-treatment to prevent cataract formation

• Apply only to affected areas — avoid healthy skin exposure

• Monitor cumulative UVA exposure to minimize long-term carcinogenesis

• Avoid use in children unless under expert supervision

• Perform baseline skin assessment and photosensitivity testing (MPD)

---

Drug Interactions

• Photosensitizing drugs (e.g., tetracyclines, sulfonamides, thiazides, NSAIDs) may potentiate UV toxicity

• Topical retinoids or keratolytics can enhance absorption and increase local irritation

• Concomitant immunosuppressants may heighten cancer risk

---

Clinical Monitoring

• Assessment of skin response (erythema, repigmentation, resolution of plaques)

• Monitor for signs of phototoxicity

• Regular dermatological exams to detect early signs of photoaging or malignancy

• Cumulative UVA dose tracking (especially in chronic diseases)

---

Comparison: Topical vs. Oral PUVA

Feature	Topical PUVA	Oral PUVA
Photosensitizer	Methoxsalen cream	Oral methoxsalen
Systemic side effects	Minimal	Nausea, hepatotoxicity, headache
UVA exposure	Localized	Whole body
Risk of phototoxicity	Lower (localized)	Higher
Indications	Localized diseases	Extensive or generalized dermatoses
Cancer risk	Lower	Higher with cumulative dosing

Patient Counseling Points

• Apply the medication exactly as directed

• Wear protective clothing and eyewear during and after therapy

• Avoid direct sunlight after application (for at least 24 hours)

• Do not apply to face, genitalia, or mucosa unless specifically instructed

• Inform clinician of any blistering, burning, or severe erythema

• Maintain follow-up appointments for clinical assessment and cumulative UV tracking

---

Regulatory and Clinical Use

• Methoxsalen and trioxsalen are included in the WHO Model List of Essential Medicines for phototherapy

• Available by prescription only (Rx) in most countries

• Use is restricted to specialist dermatology or phototherapy clinics

• Requires phototherapy equipment with dosimetry

---

Current Research and Future Directions

• Nanocarrier-based topical psoralens for enhanced delivery with reduced toxicity

• Targeted photodynamic therapy (PDT): Combining photosensitizers with lasers or LED

• Combination with immunomodulators for synergistic effect

• Evaluation of low-dose, maintenance topical PUVA for chronic conditions