Are You Confident of the Diagnosis?
What you should be alert for in the history
The diagnosis of actinic prurigo (AP) is based on the history of chronic, intensely pruritic lesions over sun-exposed skin, with frequent eyes and lip involvement, usually beginning in childhood with typical clinical findings and in some cases a familial history of the disease. In some populations HLA typing showing HLA DRB1*0407 provides support for the diagnosis. Histopathologic findings of the lips or conjuntiva are helpful as well as an excellent response to thalidomide treatment.
Characteristic findings on physical examination
On physical examination, the characteristic features are excoriated erythematous papules, crusts, lichenified plaques, hyperpigmented or hypopigmented pitted scars on sun-exposed sites, especially the face (malar regions, distal half of the nose, lips, ears) (Figure 1, Figure 2), neck, V-area of the chest (Figure 3), external regions of the arms and forearms, and dorsum of the hands (Figure 4), although any exposed site could be affected.
In some cases the lesions could extend to covered areas; such extension, which has been described in patients seen in the United Kingdom, is uncommon in Latin American patients. The affected skin could develop eczematization or seconday infection (Figure 5). In chronic cases, a marked thickening of the facial skin, sometimes associated with alopecia of the lateral eyebrows, could be found.
The lips are involved in 33-85% of the patients; most frequently affected sites are the lower lip or the central area of the upper lip, presenting with swelling, scaling, fissures, crust formation, hyperpigmentation and ulceration (Figure 6).Involvement of the eyes occurs in up to 45% of the cases, beginning with hyperemia, photophobia and increased lacrimation, progressing to brown pigmentation, papillae hypertrophy and pseudopterygium (Figure 7). In American indigenous tribes and Latin American Mestizos, there are patients with only lips and/or conjunctival lesions; in these cases, a biopsy is helpful in confirming the diagnosis.
AP runs a chronic course with exacerbation during the spring and summer months. In areas without seasonal fluctuation of sunlight, AP patients could exhibit the same lesions throughout the entire year. AP sufferers are frequently unaware of the role of sunlight in their condition because of the chronic nature of the disease; this is a distinct from patients with polymorphic light eruption (PLE), who usually are aware of the role of the sun in their disease.
Expected results of diagnostic studies
A biopsy of the lesions, especially of the lips or the conjuntiva, could help to establish the diagnosis of AP. Histologic skin findings consist of hyperkeratosis with or without parakeratosis, spongiosis, regular acanthosis and thickening of the basal membrane, dense perivascular lymphocytic infiltrate in the dermis and dermal edema. Lip and conjuntival biopsies show dense dermal lymphocytic or lymphoplasmocytic infiltrate with a band-like distribution, or lymphoid follicles with germinal centers (63-88% of the cases) (Figure 8). A variable numbers of eosinophils, mast cells and melanophages are present.
Photoprovocation of the lesions can be achieved in most cases (75-100%) with repetitive exposures to artificial ultraviolet (UV) A or UVB radiation. Minimal erythema doses (MED) of UVA and UVB are usually normal.
HLA typing is important in AP since there is a strong association in Mestizos and Caucasians with HLA DR4, particularly the subtype DRB1*0407, followed by HLA DRB1*1406 in Mexicans. However, some AP patients do not show these alleles.
Patch and photopatch tests are usually negative. Complete blood count, antinuclear antibodies, anti SSA (Ro) and anti SSB (La) antibody titers and porphyrin profiles are within normal limits or negative.
The differential diagnosis of AP include the following entitites:
Photoaggravated atopic dermatitis (personal or familial history of atopy, the presence of xerosis, sparing of the lips, sparing of the tip of the nose and eczematous lesions in the flexures help to distinguish these diseases)
Chronic actinic dermatitis (common in older men, lowered MED to UVA, UVB, may have abnormal response to visible light, and may have positive patch and photopatch tests).
Polymorphic light eruption (recurrent lesions located in sun-exposed areas that heal without scarring, frequently there is sparing of the chronically sun exposed sites. It is not associated with any particular HLA antigen, lips and conjuntiva involvement is absent. Lymphoid follicle formation is not found in skin biopsies).
Hydroa vacciniforme (occurs most commonly in children, the primary lesion is a vesicle, sometimes an hemorrhagic vesicle, which evolves to crust and usually a varioliform scar; occurs in sun-exposed areas only).
Erythropoietic protoporphyria (most commonly with onset in childhood, there is abnormal red blood cell protoporphyrin concentration).
Who is at Risk for Developing this Disease?
AP has been described mainly in Native American indigenous tribes and Latin American Mestizos, particularly in Mexico, Colombia, Perú, Bolivia, Guatemala and Honduras. There are some cases reported in Caucasian (England, Ireland, Scotland, France, Germany, Australia) and Asian (Thailand, Singapore, Japan) populations. Familial cases are frequently found in closed indigenous communities (75%); reports from Mexico have found 15% of cases being familial. An important part of history taking is to ask for Native American indigenous ancestry and whether any relatives are affected.
The prevalence of this disease in photodermatology clinics around the world varies from 0-5%; in Mexico, the prevalence is 3.5-5%. AP is more common in women than in men (2-4:1), but in reports from Asia, more men are affected. The onset is usually in childhood or before 20 years of age; however, onset in adulthood can also occur. In Latin American countries, AP most commonly affects individuals living at high altitudes (greater than 1,000 meters), although there are cases reported at the sea level. Of note, most of patients from high-altitude locations improve when they move to lower altitudes.
What is the Cause of this Disease?
The etiology of AP is still unknown; a causal role for UVR have been suggested given the distribution of the lesions, the differences on the behavior of the disease during summer and winter, and also because the lesions can be induced by artificial UVR sources. This disease is considered a delayed hypersensitivity reaction to an unidentified autoantigen induced by ultraviolet radiation, in genetically susceptible individuals.
While UVR is known to decrease the density of epidermal Langerhans cells in healthy individuals, some authors have found persistence of Langerhans cells in the epidermis after UVR exposure in AP patients, suggesting a resistance to UVR-induced immunosuppression. However, a recent study did not confirm this finding.
A study by investigators in Colombia compared cellular and humoral immunity by in vitro proliferation studies, ELISA and immunofluorescence in AP patients and healthy controls; autoimmune reactivity was found. The authors consider that AP patients may have one or more skin antigens that trigger an autoimmune response.
HLA class I and II antigens have been associated in patients with AP: HLA Cw4 in Chimila Indians of Colombia (OR: 5.2 CI: 1.8-10.2) and in Saskatchewan Cree Indians of Canada (OR: 5 CI: 1.4-14.6), B40 and Cw4 (OR: 5,2 CI: 2.1-13.5) in Mestizos of the Andean region of Colombia, A24 (OR: 6.8 CI: 2.2-20.7) in Saskatchewan Cree Indians of Canada, A28 (OR: 20.9 CI: 8.31-48.5) and B39 (OR: 6.7 CI: 3.11-13.2) in Mexican patients.
Class II HLA DR4 (OR: 10.1 CI: 2.3-91.8 in Mexicans, OR: 8.2 CI: 5-13.5 in Colombians), particularly the DRB1*0407 subtype has been the most frequent finding in patients from Mexico (OR: 12.9 CI: 6.4-26), Colombia (OR: 7.7 CI: 3.0-19.9) and the United Kingdom, followed by HLA DRB1*1406 (OR: 4.5 CI; 0.9-24.8) in Mexicans. The haplotype DRB1*0407/DQB1*0302/DPB1*0402 was found in 68.8% of Colombian patients (OR:15.4 CI: 6.7-35.9) and only in 12.5% of the controls. HLA DRB1*0802 could be a possible protective allele in Mexicans and HLA DRB1*01 and 13 in Colombian people.
Because of the strong HLA association, it is possible that HLA alleles in association to environmental factors may determine the response to a UVR-induced endogenous antigen that would trigger the characteristic lesions.
Some authors, primarily based on studies on patients in Europe and the United Kingdom, believe that PLE and AP are the same disease in patients with different genetic background, leading to a different clinical expression. This is based on the induction of the lesions with UVR in both entities, similar histopathologic findings in some skin biopsies, and the existence of AP patients with an additional personal and/or family history of PLE. However, in Latin America, AP is considered a separate entity, with characteristic epidemiologic, clinical, and histopathologic features.
Immunohistochemical studies of Mexican patients showed that keratinocytes contain abundant TNF alfa. The authors believe that UVR may trigger excessive TNF alfa production by keratinocytes, and this sustained release leads to the development of lesions; this may explain why TNF antagonists such as thalidomide are useful in the treatment of AP.
Systemic Implications and Complications
There are no systemic complications related to AP; however this disease has a major impact on the quality of life, with two-thirds of the patients showing DLQI scores >10 (moderate effect). This is due to pruritus, the appearance of the lesions, secondary scarring, and the need for sun avoidance.
There are reported cases of AP associated with PLE; AP in association with solar urticaria has been also reported, with a patient showing the characteristic clinical features of AP and developing wheals soon after sun exposure on sun-exposed sites, which disappear within minutes without leaving scars.
Treatment options are summarized in Table I.
|Medical Treatment||Surgical Procedures||Physical Modalities|
|Photoprotective measures (seeking shades, sunscreens, appropriate clothing, hats and sunglasses)||Phototherapy or photochemotherapy|
|Topical corticosteroids or calcineurin inhibitors. Cyclosporin ophthalmic drops||Pseudopterygium surgery|
|Short courses of oral corticosteroids|
Optimal Therapeutic Approach for this Disease
– Explain the natural history of AP to the patients, it is important to achieve the patient´s understanding of the disease in order to change sun exposure habits.
– Determine the severity of the condition and the effect on the quality of life.
– Every effort should be made to practice rigorous photoprotection. Encourage patients to avoid sunlight especially from 10 AM to 4 PM, seek shade while outdoors, use broad-spectrum high SPF (>30) sunscreens, wear sunglasses, appropiate clothing, broad-brimmed hat, and avoid standing or working by the windows (since UVA is transmitted through window glass). In countries where it is available, the application of a UV protective film on home and car windows is helpful to minimize transmission of UVA.
– In some cases, topical potent corticosteroids are helpful; of course, their chronic use should be avoided. They can be substituted by tacrolimus 0.1% ointment, or pimecrolimus cream. These are useful for secondary eczematization.
– A short course of oral corticosteroids will control acute flares, but one should be mindful about the potential rebound after the completion of the oral corticosteroids. To minimize rebound, begin with mild topical corticosteroids, or topical calcineurin inhibitors, for the remaining lesions.
– For secondary infection, use topical antibiotics (fusidic acid, mupirocin), and if need be, oral antibiotics.
– A prophylactic course of narrowband UVB or PUVA in springtime (3 weekly sessions for 5 weeks, beginning with 70% MED, increasing 20% every session, is beneficial for some patients. The patient must continue to maintain the desensitization with regular sun exposure (up to 20-30 minutes of midday sun, without sunscreen if tolerated) in order to avoid new lesions. It should be noted that in Latin America, phototherapy is not as useful as has been described in other regions.
– Currently, the best treatment for AP is thalidomide, a synthetic derivative of glutamate acid, with immunomodulatory and antiinflammatory effects (inhibits the synthesis of TNF alfa in monocytes, decreases TNF alfa serum levels and modulates the IFN gamma producing CD3+ cells). The initial recommended dose is 100-200mg/day, depending on the severity of the disease. Usually, beneficial effects are noted within 50 days; however, lesions may recur upon discontinuation; therefore, it is best to taper the dose slowly. Many patients could control the disease with a dose of 25-50mg/week.
– Cyclosporine eyedrops are helpful for ocular involvement. In some cases, ophthalmologic surgery is needed to remove the pseudopterygium.
– Pentoxifylline has been reported as useful in one uncontrolled study.
Explain to patients and their families the natural chronic course of the disease, the possible involvement of eyes and lips, and the different treatment options available. Educate the patient and the family about photoprotection; inform them that even with photoprotection, flares may still occur.
In mild cases, topical corticosteroids and tacrolimus ointment are usually sufficient to control the disease.
Some patients experience benefit with a course of phototherapy, however, flares are common during this desensitization courses, therefore, the use of potent topical corticosteroids or, if need be, a short course of oral corticosteroids (1mg/kg for 1 – 2 weeks with rapid taper, start at the initiation of phototherapy) is recommended.
Although thalidomide is the best treatment known for this disease, there are various adverse effects that the patient should know and prevent. Thalidomide is teratogenic, so women of child-bearing age should use effective contraception methods, starting at 4 weeks before the initiation of the treatment and continuing until 4 weeks after ending it.
In the United States, only physicians and pharmacists registered with the System for Thalidomide Education and Prescription Safety (S.T.E.P.S.) are allowed to prescribed and dispense the medication; strict guidelines for effective contraception and monitoring of pregnancy test must be followed in women of child-bearing potential.
With thalidomide, peripheral neuropathy could occur, which usually begins with symmetrical painful paresthesias of the hands and feet with sensory loss in the lower extremities. The neuropathy can resolve slowly or may be irreversible. Baseline nerve conduction studies are recommended to monitor for the subclinical development of peripheral neuropathy. Follow-up testing is suggested after every 10g cumulative dose or every 6 months. If a fall from baseline values of more than 40% on repeat testing is detected, the treatment should be discontinued.
Thromboembolic complications have been reported with thalidomide, particularly in patients with cancer. It is best to take this medication at night because it can produce sedation; however, this side effect diminishes over time.
Despite the adverse effects described, thalidomide is usually well tolerated, and peripheral neuropathy had been only rarely reported in most of the AP treatment series.
Unusual Clinical Scenarios to Consider in Patient Management
Unfamiliarity with the condition could lead to incorrect diagnosis; being aware of the natural history of the disease and the clinical features will help the clinician to recognize this cases.
In tropical countries, people are exposed to sunlight all year round; therefore, it may be difficult to make the distinction between persistent PLE and AP, particularly in late onset AP cases. The presence of scars and lip involvement points to AP. In adults, it is almost impossible clinically to distinguish ocular changes due to chronic sun exposure from those associated to AP; therefore, a conjunctival biopsy is helpful.
Difficulty in sunlight avoidance due to a patient´s job, habits and/or socioeconomic conditions would slow down the disease improvement.
Some indigenous patients have their own beliefs related to the disease; therefore, it would be difficult to change sun exposure habits and to make them follow the treatment.
There are countries where thalidomide is not available or is difficult to obtain. Therefore, alternate treatments may be needed. In severe cases, cyclosporine has been reported to be beneficial.
What is the Evidence?
Honigsmann, H, Hojyo-Tomoka, MT, Lim, H, Honigsmann, H, Hawk, JLM. “Polymorphous light eruption, hydroa vacciniforme and actinic prurigo”. Photodermatology. 2007. pp. 159-67. (A complete review of the epidemiology, etiology and pathogenesis, clinical features, histopathologic aspects, diagnostic clues and treatment of AP.)
Vega-Memije, ME, Mosqueda-Taylor, A, Irigoyen-Camacho, ME, Hoyjo-Tomoka, MT, Dominguez-Soto, L. “Actinic prurigo cheilitis: clinicopathologic analysis and therapeutic results in 116 cases”. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. vol. 94. 2002. pp. 83-91. (This retrospective study included 116 patients with AP cheilitis, with a complete description of the clinical and histopathologic findings and also the response to treatment in these patients.)
Torres-Alvarez, B, Baranda, L, Fuente, C, Dergado, C, Santos-Martìnez, L, Portales-Perez, D. “An immunohistochemical study of UV-induced skin lesions in actinic prurigo. Resistance of Langerhans cells to UV light”. Eur J Dermatol. vol. 8. 1998. pp. 24-8. (The expression of cell adhesion molecules and the density of Langerhans cells in UVR induced lesions of AP patients were studied. The authors found an increased expression of adhesion molecules and persistence of Langerhans cells in the epidermis after UVR.)
Calderon-Amador, J, Flores-Langarica, A, Silva-Sanchez, A, Donis-Maturano, L, Granados, J, Vega Memije, E. “Epidermal Langerhans cells in actinic prurigo: a comparison between lesional and non lesional skin”. J Eur Acad Dermatol Venereol. vol. 23. 2009. pp. 438-40. (A recent study that compared epidermal Langerhans cell densities in punch biopsy specimens from lesional and non lesional skin of AP patients. The results showed a decrease of Langerhans cells in lesional skin.)
Gomez, A, Umaña, A, Trespalacios, AA. “Immune responses to isolated human skin antigens in actinic prurigo”. Med Sci Monit. vol. 12. 2006. pp. 106-13. (The authors compared cellular and humoral immunity by in vitro proliferation studies, ELISA and immunofluorescence test in AP patients and helathy controls, finding autoimmune reactivity in AP patients.)
Suarez, A, Valbuena, M, Rey, M, Porras, L. “Association of HLA subtype DRB1*0407 in Colombian patients with actinic prurigo”. Photodermatol Photoimmunol Photomed. vol. 22. 2006. pp. 55-8. (A Colombian study confirming the HLA DRB1*0407 association with AP and the importance of indigenous ancestry in the disease.)
Grabczynska, SA, McGregor, JM, Kondeatis, E, Vaughan, RW, Hawk, JLM. “Actinic prurigo and polymorphic light eruption: common pathogenesis and the importance of HLA-DR4/DRB1*0407”. Br J Dermatol. vol. 140. 1999. pp. 232-6. (This study highlights the importance of HLA typing in AP, and the difficulty in some cases in making a definite diagnosis due to overlapping clinical features between PA and persistent PLE.)
John, CT, Finlay, AY, Pearse, AD, Kerr, AC, Ferguson, J, Benton, EC. “The quality of life of 790 patients with photodermatoses”. Br J Dermatol. vol. 159. 2008. pp. 192-7. (An interesting study showing how sun induced dermatoses affect the quality of life.)
Londoño, F. “Thalidomide in the treatment of actinic prurigo”. Int J Dermatol. vol. 12. 1973. pp. 326-8. (This was the first study in which thalidomide was used for the treatment of AP.)
Wu, JJ, Huang, DB, Pang, KR, Tyring, SK. “Thalidomide: dermatological indications, mechanism of action and side effects”. Br J Dermatol. vol. 153. 2005. pp. 254-73. (A complete review of all the aspects of thalidomide, including its therapeutic uses in dermatology and the guidelines for using it.)
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