Actinic Prurigo

Background

Actinic prurigo (AP) is a chronic, pruritic skin disease caused by an abnormal reaction to sunlight. In 1954, Escalona first described it in Mexico. Lesions appear hours or days following sun exposure, contrary to what happens in solar urticaria where skin lesions appear minutes after UV exposure. It is commonly associated with cheilitis and conjunctivitis.

Pathophysiology

No systemic or local photosensitizer is known in patients with AP, and a hypersensitivity implicating immunoglobulin E (IgE) has not been demonstrated.

AP has many features of a type IV hypersensitivity reaction. Skin lesions associated with AP are infiltrated with T lymphocytes, mostly CD4⁺, and some of the T-cells express activation markers. AP falls in the category of autoimmune diseases because lymphocytes from patients have been proven to be stimulated in a thymidine incorporation assay when confronted with their own UV-irradiated keratinocytes or UV-irradiated epidermal homogenates.

At this point, the antigen that provokes the inflammatory reaction is not clear, but an epidermal protein is believed to be transformed by UV exposure. In the series by Santos-Martinez et al, the presence of transforming growth factor-beta interleukin 13, and interleukin 10 was demonstrated in a non–type-TH1, non–type-TH2 pattern, similar to what has been shown in lesions of psoriasis and in the synovial fluid of rheumatoid arthritis.

Another potentially important finding in the pathogenesis of AP may be the fact that Langerhans cells in persons with AP show resistance to UV exposure when compared with those in healthy individuals.This same finding has been shown in patients with a similar disease, polymorphous light eruption (PLE). Because these cells are resistant to their demise after UV exposure, they might handle and deliver UV-modified cutaneous antigens to T cells in larger amounts or in a more persistent way; this process could cause or augment the inflammatory phenomenon that is observed in the skin of patients with AP. The apoptotic mechanism in these cells may be somewhat altered, facilitating their survival.

On the other hand, the polyclonal cellular immune response found in biopsy samples from Mexican patients through Southern blot analysis may involve an imbalance linked to a specific hyperimmunity, in which the proportion of autoimmune cells is increased and the proportion of other cells is decreased.

Although different series are searching for a specific HLA, studies have shown associations with B40 and CW3 alleles in some populations, especially Amerindians. For instance, in the Chimila Indians from Colombia,a high frequency of HLA-Cw4 was found. However, in Cree Indians from Saskatchewan, Canada, the most common antigens were HLA-A24 and HLA-Cw4.

Other studies have shown a strong association with HLA-DR4. The more precise finding appears to be in the Mexican series, in which HLA-DR4 DRB1*0407 is found in more than 90% of patients with AP.Another series also found HLA-DR4 DRB1*0407 in Colombian patients. Related alleles such as DRB*0407 have been found in British populations,and DRB1*14 has been found in the Inuit Indians of Canada.

English patients with polymorphic light eruption (PMLE) have not shown an association with any HLA, which suggests that HLA-DR4 (DRB1*0407) could be used as a marker to distinguish PMLE from AP. Therefore, the association with HLA in AP but not in PLE suggests that AP represents an immunologically mediated disease with strong genetic determinants for its expression.

Frequency

United States

AP occurs in persons of all skin types, but its prevalence in the general population is unknown. It probably represents less than 5% of referrals to photodermatologic clinics.AP is well known in the United States among Native Americans.

International

In Mexico, AP represents 1.34% of consultations with pediatric dermatologists and 4% of consultations with general dermatologists. AP is common in Mexico, Central America, and South America, and it is well known in Canada among Native Americans.AP rarely occurs in Europe and Asia, where PLE (a disease with pathogenetic features similar to AP) is more regularly seen. Isolated cases have been reported in France,Germany, Japan, Singapore, Thailand,and Australia. However, the prevalence rate of AP in photodermatology clinics around the world varies from 0-5%.

Mortality/Morbidity

AP is not associated with mortality.

Race

AP frequently affects mestizos of Latin America and American Indians with skin phototypes IV or V.

Sex

In children and adolescents, no differences in prevalence exist between the sexes. However, in adults, women are more frequently affected than men, with a female-to-male ratio of 2:1.

Age

AP can occur at any age; however, one third of patients are children.

Treatment

Medical Care

• The cornerstone of pharmacologic treatment is 100 mg/d of thalidomide. Studies have shown that this drug modulates its effect on PA through suppression of tumor necrosis factor-alpha synthesis and modulation of interferon-gamma–producing CD3⁺ cells.Thalidomide can be gradually reduced and then reinstituted in cases of relapse. Women in their childbearing years must use contraceptives because of the teratogenic potential of thalidomide. On some occasions, topical steroids or immunosuppressors are indicated, especially in acute exacerbated cases. Once the skin lesions remit, sunscreens should be used.

• Other medications frequently used with moderate results, because of their anti-inflammatory action, are antimalarials and pentoxyphilline,although these drugs are more useful as topical corticosteroid-sparing agents.

• Less favorable results are obtained with antihistaminics, beta-carotenes, and psoralen plus UV-A light.

• If complications (eg, secondary infection, eczema) occur, patients can be treated with oral antibiotics or topical Burow solution.

Activity

Patients affected by AP should not have restrictions in any areas, such as employment and education. However, changing from outdoor to indoor occupations is important if the patient is not improving with treatment.

Medication

Treatment is mainly aimed at avoiding sun exposure. However, oral and topical corticosteroids are frequently used for short periods. Thalidomide is used, either alone or with topical corticosteroids, for resistant or multiple relapse cases.

Drug Category: Immunosuppressant agents

These agents inhibit key steps responsible for initiating immune activity.

Drug Name	Thalidomide (Thalomid)
Description	Immunomodulatory agent that may suppress activated lymphocytes or prevent their activation. Also down-regulates excessive production of tumor necrosis factor-alpha and selected cell-surface adhesion molecules involved in leukocyte migration.
Adult Dose	100-300 mg/d PO qd with water, preferably hs and at least 1 h pc <50>
Pediatric Dose	0.5-2.5 mg/kg/d PO qd with water
Contraindications	Documented hypersensitivity
Interactions	May increase sedation of alcohol, barbiturates, chlorpromazine, and reserpine; because of teratogenic effects, women must use 2 additional methods of contraceptives or abstain from intercourse
Pregnancy	X - Contraindicated in pregnancy
Precautions	Perform pregnancy test within 24 h prior to initiating therapy (weekly during the first month, followed by monthly tests in women with regular menstrual cycles or q2wk in women with irregular menstrual cycles); bradycardia may occur; use protective measures (eg, sunscreens, protective clothing) against exposure to sunlight or UV light (eg, tanning beds); prescribing physician must enter STEPS program established by manufacturer

Drug Category: Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Name	Prednisone (Orasone, Meticorten, Sterapred, Deltasone)
Description	Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes.
Adult Dose	0.5-2 mg/kg/d PO; taper as condition improves; single morning dose is safer for long-term use, but divided doses have more anti-inflammatory effect
Pediatric Dose	4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve
Contraindications	Documented hypersensitivity; viral, fungal, connective tissue, or tubercular skin infections; peptic ulcer disease; hepatic dysfunction; GI bleeding or ulceration
Interactions	Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Name	Betamethasone (Diprolene, Maxivate, Alphatrex)
Description	For inflammatory dermatoses responsive to steroids. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability. Affects production of lymphokines and has inhibitory effect on Langerhans cells.
Adult Dose	Apply thin film bid/qid until response
Pediatric Dose	Apply as in adults with caution
Contraindications	Documented hypersensitivity; paronychia; cellulitis; impetigo; angular cheilitis; erythrasma; erysipelas; rosacea; perioral dermatitis; acne
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Do not use in skin with decreased circulation; can cause atrophy of groin, face, and axillae; may cause striae distensae or rosacealike eruption; may increase skin fragility; rarely may suppress HPA axis; if infection develops and is not responsive to antibiotic treatment, discontinue until infection is under control; do not use monotherapy to treat widespread plaque psoriasis

Drug Category: Antimalarial agents

These agents are used for their anti-inflammatory and photoprotective effects.

Drug Name	Hydroxychloroquine (Plaquenil)
Description	Exerts anti-inflammatory activity by suppressing lymphocyte transformation and may have photoprotective effect. Use in AP requires small doses once a day for long periods.
Adult Dose	200 mg/d PO qd to bid
Pediatric Dose	4 mg/kg/d PO once
Contraindications	Documented hypersensitivity to 4-aminoquinoline derivatives; psoriasis; retinal and visual field changes attributable to 4-aminoquinolines
Interactions	Cimetidine may increase serum levels of chloroquine (possibly other 4-aminoquinolones); magnesium trisilicate may decrease absorption of 4-aminoquinolones
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic disease, G-6-PD deficiency, psoriasis, or porphyria; not recommended for long-term use in children; perform periodic ophthalmologic examinations; test for muscle weakness; retinopathy, tinnitus, nerve deafness, skin eruption, headache, anorexia, nausea, vomiting, and diarrhea may occur

Drug Name	Chloroquine phosphate (Aralen Phosphate)
Description	Inhibits chemotaxis of eosinophils and locomotion of neutrophils, and impairs complement-dependent antigen-antibody reactions. May also have photoprotective effect.
Adult Dose	250-600 mg PO qd
Pediatric Dose	Not established; 4 mg/kg/d PO can be used
Contraindications	Documented hypersensitivity; psoriasis; retinal and visual field changes attributable to 4-aminoquinolones
Interactions	Cimetidine may increase serum levels of chloroquine (possibly other 4-aminoquinolones); magnesium trisilicate may decrease absorption of 4-aminoquinolones
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic disease, G-6-PD deficiency, psoriasis, or porphyria; not recommended for long-term use in children; perform periodic ophthalmologic examinations; test for muscle weakness; retinopathy, tinnitus, nerve deafness, skin eruption, headache, anorexia, nausea, vomiting, and diarrhea may occur