Topical treatment of cutaneous lupus erythematosus (CLE) has undergone far less scientific evaluation than systemic therapeutic modalities. Nevertheless, in many cases in which LE is confined to the skin and disease extension is limited to a few areas, local therapy and avoidance of triggering factors may be sufficient to effica- ciously control the cutaneous manifestations. In extensive cases and systemic disease with skin involvement, topical therapy is an important addition to systemic therapy in the strategy to keep the complex disease under control. Therefore, management of CLE depends on the subset and on the severity and the extension of the disease in the individual patient, and it usually has to include a combination of local measures and systemic pharmaceuticals (Lo et al. 1989, Ting and Sontheimer 2001, Werth et al.
1997).
The local measures encompass topical medications as well as avoidance of disease- triggering factors, of which ultraviolet (UV) irradiation is the most important and the best studied. Other environmental triggers include cold, heat, and mechanical stress, which also may provoke skin lesions in LE and are far less studied than ultraviolet (UV) irradiation (Baer and Harber 1965, Ueki 1994).
Topical Corticosteroids
Application of topical corticosteroids (CSs) is part of the standard external therapy in CLE. Alone or in combination with systemic anti-inflammatory agents, CSs are very effective in reducing the main symptoms of the skin lesions of LE, namely, red- ness and squamae. To be effective in LE, intermediate (e. g., triamcinolone acetonide) to potent or superpotent CS preparations (betamethasone dipropionate, halobetasol propionate, fluocinonide, and clobetasol propionate) have to be used to achieve sig- nificant amelioration of the skin lesions. Usually, potent CS preparations should not be used on the face since the well-known side effects (atrophy, telangiectasias, steroid dermatitis, and folliculitis) tend to be especially severe in facial skin. However, in view of the risk-benefit ratio, CLE represents an exception to that rule, since the facial skin lesions of LE are often exceedingly disfiguring so that the CS side effects are less troublesome. Twice-daily application for a few weeks followed by a rest period of a few weeks may help minimize the risk of local side effects.
The choice of the vehicle for the CS treatment is important, for example, ointment- based products have a greater effectiveness since they induce stronger hydration of the skin with greater delivery of the CS through the horny layer into the skin. At the
Topical Treatment
of Cutaneous Lupus Erythematosus
Percy Lehmann
25
same time, these preparations are especially suitable for hypertrophic lesions, as they effectively ameliorate the stubborn hyperkeratosis of LE.
Creams may be cosmetically more acceptable for some patients, but they also may be more irritating owing to the emulsifiers, preservatives, and fragrances that most of them contain. For scalp lesions, CS solutions and gels are best applied since they can also be easily washed off with standard shampoos. For scalp lesions, the CS side effects are less harmful since the skin in this area seems to be less sensitive, especially regarding atrophy and telangiectasias. Potent CS preparations, therefore, may be applied here deliberately.
To enhance the efficacy of CSs, occlusive therapy may be chosen, especially for scalp lesions (e. g., shower cap). Different occlusive techniques exist for the various skin areas, which all can be applied overnight for maximum efficacy. Plastic food wrap (saran wrap) or adhesive gas-permeable surgical dressings (TegaDerm) can be used for larger areas on the trunk and extremities. For the hands, vinyl-over-cotton gloves (two-layered glove technique) can be recommended. If only the fingers are affected, rubber finger cots are available for occlusion.
To further increase CS efficacy and to achieve maximal drug concentrations in the active lesion, intralesional therapy may be chosen. Especially in hyperkeratotic dis- coid LE (DLE) and other refractory lesions, intralesional CS application may lead to better treatment responses. The concentration of the CS has to be adjusted to the site of injection, that is, 2.5–5 mg/mL triamcinolone acetonide suspension for the face and up to 10 mg/mL for other sites like the scalp or extremities. Intralesional CS applica- tion has long-lasting effects and may not be repeated until 4–6 weeks after the previ- ous injections. To avoid subcutaneous atrophy, the injections should be placed in the dermis and not in the subcutaneous fat.
Dermatosurgical and Laser Therapy in Cutaneous Lupus Erythematosus
In patients with treatment-resistant lesions, different surgical techniques may offer additional alternatives. For many years, cryotherapy has been used to treat LE lesions;
however, systematic studies are lacking, and the reported numbers in treatment series are low (Ting and Sontheimer 2001). Further surgical techniques that have been reported in individual cases include dermabrasion, laser resurfacing, hair trans- plantation, and surgical excision of disfiguring lesions. Owing to the disease-specific nature of LE, a test area should probably be treated first so that avoidance of the Koebner phenomenon and adequate healing may be ensured.
Vascular lesions with telangiectasias on visible areas, such as the face, are common in DLE; however, efficient management of these skin lesions can sometimes be diffi- cult. Since argon laser light can specifically coagulate vascular structures, it has been used in the treatment of various vascular skin malformations. Effective use of argon laser has been reported by two groups (Kuhn et al. 2000, Zachariae et al. 1988) (Table 25.1).
Single observations in the literature revealed successful treatment of cutaneous vas- cular lesions of LE with the carbon dioxide and the pulsed dye laser. In 1986, Henderson and Odom (Henderson and Odom 1986) treated characteristic plaques of
a patient with DLE by using the carbon dioxide laser and observed a dramatic clinical and cosmetic improvement in the cutaneous lesions. Hypopigmentation in the tested areas and reactivation of DLE in the periphery were described as side effects. Nunez et al. (Nunez et al. 1995, 1996) described telangiectatic chronic erythema of cutaneous lesions in four patients with systemic LE (SLE) who had been successfully treated with the flashlamp pulsed dye laser operating at 585 nm. Recently, Raulin et al. (Raulin et al.
1999) described a group of 12 patients with different forms of LE who were treated with the pulsed dye laser. A clearance rate was attained in 70% of the patients, and even in the two patients with SLE, a significant improvement was achieved. None of these patients showed any prolonged laser-induced scarring.
In 1988, Zachariae et al. (Zachariae et al. 1988) reported for the first time the treat- ment of cutaneous vascular lesions in connective tissue diseases with the argon laser.
They noticed significant blanching of the patches, although scarring and hyperpig- mentation remained. Since then, only one further report in the German literature (Nurnberg et al. 1996) documented successful treatment with the argon laser of skin lesions on the extensor aspect of the arms in one patient with chronic DLE. In con- trast, Wolfe et al. (Wolfe et al. 1997) suggested that overtreatment with an argon laser
Table 25.1.Treatment of lupus erythematosus (LE) with laser: review of the literature. (Modi- fied after Kuhn et al. 2000)
Year Authors Indication Type Response Side effects
(number of of laser patients)
1986 Henderson DLE (1) Carbon Dramatic Splotchy
and Odom dioxide clinical and hypopigmen-
laser cosmetic tation
improvement
1988 Zachariae DLE (5) Argon laser Cosmetically 60%–70% per-
et al. satisfactory manent
result bleaching 1995 Nunez et al. LE teleangi- FPDL Excellent None
ectoides (1) improvement
1996 Nunez et al. SLE (4) FPDL Clearance in Slightly tran-
>75% sient hyper- pigmentation 1996 Nurnberg et al. DLE (1) Argon laser Clinical and Hypopigmen-
histologic tation improvement
1999 Raulin et al. DLE (8) FPDL Clearance Transient
CLE (1) rate of 70% hyperpigmen-
SCLE (1) tation SLE (2)
2000 Kuhn et al. DLE (1) Argon laser Complete None resolution
of lesions
CLE, cutaneous LE; DLE, discoid LE; FPDL, flashlamp pulsed dye laser; SCLE, subacute CLE;
SLE, systemic LE.
has the potential to induce DLE since thermal injury seems to have caused the Koeb- ner phenomenon in a patient without any previous history of autoimmune disease.
The induction of such isomorphic skin changes after cutaneous injury in previously uninvolved skin has been associated with DLE (Ueki 1994, Wolfe et al. 1997).
The argon laser seems to be a promising alternative for the treatment of vascular DLE skin lesions, with an excellent cosmetic result. However, the indication must be carefully evaluated and the risks and benefits should be precisely documented, as skin texture changes and scarring might occur
Experimental New Topical Therapeutic Agents
Since retinoids have been shown to possess anti-inflammatory and antiproliferative as well as regulatory capacity on keratinocyte differentiation, they are good candi- dates to be beneficial in LE. In fact, various topical and systemic retinoids have been reported to be effective in patients with subacute CLE (SCLE) and chronic CLE (Werth et al. 1997). However, systematic controlled studies are lacking here too.
Tazarotene, the receptor-selective topical representative of the novel acetylenic retinoids, has been very effective in the treatment of an otherwise untreatable patient with DLE (Edwards et al. 1999). Further studies are needed to evaluate the role of topical retinoids in LE.
Another very promising development in topical dermatotherapy are the calcineurin inhibitors. Tacrolimus and pimecrolimus are prototypes of a class of immunosuppres- sive agents with a great potential in the treatment of inflammatory skin diseases,atopic dermatitis above all, but also in cutaneous autoimmune diseases. These pharmaceuti- cals have been shown to act at a point in activation of T lymphocytes that lies between T-cell receptor ligation and the transcription of early genes. Therefore, besides atopic dermatitis, all T-cell-mediated skin diseases, such as lichen planus, represent a poten- tial area of use. Animal studies have demonstrated a beneficial effect of systemic tacrolimus in murine SLE (Furukawa et al. 1995). Similarly, systemic application of tacrolimus was used successfully in patients with SLE whose active disease had been poorly controlled by conventional treatments (Ruzicka et al. 1999). Consequently, top- ical calcineurin inhibitors were applied to treat the malar rash of SLE,with good results in three patients (Kanekura 2003).Anecdotal reports also demonstrated good efficacy of tacrolimus and pimecrolimus in patients with severe recalcitrant chronic DLE (Furukawa et al. 2002, Walker et al. 2002, Yoshimasu et al. 2002, Zabawski 2002), SCLE (Bohm et al. 2003, Druke et al. 2004), and LE tumidus (Bacman et al. 2003). Taken together, preliminary reports show very promising effects of this highly interesting new generation of topical treatment modality in dermatotherapy for cutaneous auto- immune disease, which urgently needs systematic evidence-based study evaluation.
Sunscreen and Photoprotection:
Current Status and Perspectives
Since clinical data, phototesting procedures, and experimental evidence demonstrate unequivocally the detrimental effects of sun irradiation on patients with LE, sun-
screens and photoprotection are major issues in the management of patients with LE (Furukawa et al. 1990, Lehmann et al. 1990, Norris 1993, Sontheimer 1996). Photopro- tection can be achieved by topical and systemic agents as well as by behavioral meas- ures, which have to be taught to the patient (Gil and Kim 2000, Lehmann 1996, Lehmann and Ruzicka 2001).
Sunscreens
Sunscreens have been developed to prevent the short- and long-term damaging effects of UV irradiation. However, the sun protective factor (SPF), which is defined as the ratio of the minimal erythema dose (MED) of sun-protected skin divided by the MED erythema of non-sun-protected skin, gives only a quantitative level of pro- tection against sunburn and edema. Therefore, there is an ongoing debate on the potency of sunscreens to protect against many other deleterious biological UV effects such as photoimmunosuppression, skin aging, or skin cancer. Recent efforts have been directed toward determining the end points of sunscreen efficacy, such as immune protection factor (IPF), mutation protection factor (MPF), and protection against photocarcinogenesis (Gil and Kim 2000). Although standardized phototest procedures are available and can be used as tools to evaluate the protective effects of sunscreens toward UV induction of LE lesions, studies addressing this important topic are lacking. Sunscreens may be subdivided into products using UV filters on a physical or a chemical base. Physical agents used in sunscreens are titanium dioxide, zinc oxide, talcum, kaolin, bentonide, silica, and mica, which protect against UVB and UVA irradiation. Physical sunscreens show, contrary to chemical filters, no potential for phototoxicity or allergenicity, and they are photostable, cost effective, and appli- cable to children as well as adults. Most physical sunscreens contain ZnO or TiO2and are referred to as physical blockers because they provide at specified concentrations high SPF protection through absorption, scattering, and reflection of UV radiation in a wide spectral range. Especially since the development of micronized formulations of ZnO and TiO2, the cosmetic acceptability of physical sunscreens has increased, and physical sunscreens have gained growing interest. Chemical agents most often used include aminobenzoates (para-aminobenzoic acid), cinnamates (diethanolamine p-methoxycinnamate [Parsol]), salicylates (2-ethylhexyl salicylate), and benzophe- nones (dioxybenzone, sulisobenzone, and oxybenzone). Most chemical blockers con- tain a combination of different filters to block a higher percentage and a broader range of UV rays. Owing to different absorption peaks, chemical filters may protect against UVB alone, UVA alone, or combined UVB and UVA (Table 25.2). There are several hundred sunscreen formulations containing different UV-protective chemi- cals on the market. However, it is important to have the photoreactivity of a broad- band absorbing sunscreen, which protects against UVB as well as UVA and exerts a high SPF (>15). This type of sunscreen has combinations of UVA and UVB filters and sometimes ZnO and TiO2.
Additional UV-Protective Chemicals
Further compounds are included in sunscreens to exert their effects in different ways than mere absorption and scattering of UV radiation. Since knowledge of the mole-
cular events of UV damage is increasing rapidly, a variety of different compounds that may interfere with these events are likely to be used increasingly in sunscreens.
Antioxidants
Since UV-induced generation of oxygen radicals seems to be an important mecha- nism for a variety of detrimental UV effects, inclusion of antioxidants and scavengers in sunscreens should provide additional UV protection. Vitamin C (ascorbic acid) and vitamin E (α-tocopherol) are the most prominent antioxidants used in sun- screens. Asorbic acid has been reported to prevent UVB-induced radical damage, secretion of proinflammatory cytokines by UVA, UV-induced suppression of sys-
Table 25.2. Sunscreen Filters UVB chemical sunscreens Aminobenzoates
p-Aminobenzoic acid (PABA) Amyl dimethyl PABA Glyceryl PABA 2-ethylhexyl PABA Cinnamates
2-ethoxyethyl p-methoxycinnamate (Parsol) Diethanolamine p-methoxycinnamate Salicylates
Octyl salicylate Trolamine salicylate 2-ethylhexyl salicylate Homomenthyl salicylate Triethanolamine salicylate Miscellaneous
Digalloyl trioleate
Lawsone with dihydroxyacetone Glyceryl aminobenzoate UVA chemical suncreens Benzophenones
Oxybenzone Sulisobenzone Dioxybenzone Miscellaneous
Menthyl anthralinate Eusolex 2020
Dibenzoyl methane (Parsol 1789, Avobenzone) UVB and UVA physical sunblocks
Kaolin
Magnesium silicate Magnesium oxide Red veterinary petrolatum Titanium dioxide Iron oxide Zinc oxide
temic contact hypersensitivity, and UV-induced activation of ERK1/2 and p38 activa- tion (Steenvoerden and Beijersbergen van Henegouwen 1999, Tebbe et al. 1997).
Tocopherol inhibits UVB-induced erythema, photocarcinogenic DNA damage, and suppression of local contact hypersensitivity, as well as depletion of Langerhans cells (McVean and Liebler 1997, Trevithick et al 1992, Yuen and Halliday 1997).
Tocopherol and ascorbic acid in sunscreens showed a significant effect on the reduction of UV-induced sunburn cells (apoptotic keratinocytes) (Darr et al. 1996).
Prophylactic use of the antioxidants ofα-glycosylrutin, ferulic acid, and tocopheryl acetate in different concentrations showed a significant reduction in polymorphic light eruption lesions and pruritus, proven by photoprovocation tests (Hadshiew et al.
1997). Although a similar effect in LE seems conceivable, no such study has been pub- lished.
Future Developments
Epidermal DNA is probably the molecule that converts the physical energy of UV into a biological signal, thus leading to immunodysregulation. Liposome-encapsuled T4 endonuclease V, which increases the rate of pyrimidine dimer repair, can prevent UV- induced suppression of delayed-type hypersensitivity (Yarosh et al. 1999). Thus, repair of UV radiation-induced DNA damage through topical application of DNA repair enzymes seems to be a promising approach to reverse damaging UV effects.
Stege et al. (Stege et al. 2000) demonstrated that application of the DNA repair enzyme photolyase in liposomes after UV irradiation induced dimer reversal and restored normal immune status. Whereas the potential of DNA repair enzymes as adjuvants in sunscreens or after sun lotions to prevent photocarcinogenesis is obvi- ous, the ability of these chemicals to prevent photoinduction of LE remains unclear.
Since DNA damage is believed to be crucial for the initiation of UV-induced autoim- munity, this approach is worth testing in UV-induced LE. Therefore, future develop- ment of sunscreen products should take the current knowledge of the pathophysio- logy of UV-induced LE into consideration to achieve more specifically tailored photoprotective agents.
General Photoprotection Measurements
The use of sun-protective clothing is especially recommended for individuals with extreme photosensitivity. The availability of fabrics with a wide choice of colors, weaves, and textures has led to increased popularity of this protective measure. The proven and documented high SPF values of modern sun-protective clothing ensure adequate protection as an adjunctive measure. Tightly knit fabric made of cotton blend is preferable to clothing of synthetic fibers because they lead to high tempera- ture and humidity, which also may adversely affect patients with LE.
Conclusion
As mentioned earlier, many patients with LE are unaware of the detrimental effects of the sun on their disease and are ignorant about simple ways to avoid them. Therefore,
education on sun protection, in addition to specific measures like sunscreens and photoprotective clothing, is of special value for patients with LE. Consequent protec- tion against UV and other physical and mechanical injuries may prevent induction and exacerbation of the disease. Although no formal studies exist to demonstrate the beneficial effects of such measures, clinical experience strongly supports this strategy. In view of the available data indicating deleterious effects of UV irradiation on LE, objective evaluation of treatment and prophylactic strategies, e. g., appropriate sunscreens, is urgently needed for better care of the patients. With the development of standardized phototest protocols, excellent tools are available for the performance of such studies. However, photoprotection and skin care in patients with LE go beyond the use of sunscreens taking into consideration that LE-specific lesions can be precipitated in nonlesional skin by a variety of nonspecific injuries (Koebner phe- nomenon), including mechanical traumas, heat, cold, etc., a poorly studied fact (Walker et al. 2002).
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