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Cutaneous lupus erythematosus may be a manifestation of systemic lupus or may occur independently of systemic disease. It requires specific management by dermatology specialists.
THE VARIOUS FORMS OF CUTANEOUS LUPUS ERYTHEMATOSUS
The dermatological lesions observed in patients with cutaneous lupus erythematosus may be specific or non-specific. How the lesions develop and the risk of sequelae vary depending on the type of lesions. A dermatology specialist must be called on to analyse the situation and to precisely characterise the type of lesions and determine a suitable treatment strategy. Non-specific cutaneous lesions are often associated with the inflammatory or thrombotic vascular lesions sometimes observed with the antiphospholipid syndrome associated with lupus. These lesions appear in a particular context that will not be broached here.
The specific lesions associated with lupus may be divided into three groups as a function of their development, i.e. acute, subacute and chronic lesions.
ACUTE LUPUS ERYTHEMATOSUS LESIONS
The lesions are red and more or less oedematous or squamous (covered with fine scales or skin flakes). Some forms of acute lupus are localised with lesions occurring mainly on the cheeks and nose producing a rash in the shape of a butterfly (giving patients a wolf bite-like appearance) and on the forehead, neck and chest. Other forms produce more diffuse lesions that may call to mind a skin reaction to a medicinal product or a viral infection such as measles. The lesions of acute lupus evolve in a comparable way to the lesions of systemic lupus erythematosus and disappear similarly to them without leaving scars. The management of acute lupus erythematosus lesions is identical to that of systemic lupus erythematosus, but the subject is not broached in this chapter.
SUBACUTE LUPUS ERYTHEMATOSUS LESIONS
Subacute lupus is characterised by pink or red, more or less thick lesions that change to become annular or squamous in appearance, covered by a superficial white skin membrane. Both types of lesions may be observed together in the same patient. Subacute lupus lesions frequently occur on the face and resemble those of acute lupus, which leads to frequent confusion between the two forms of the disease. Diagnosis should be based on the clinical features and not the location of the lesions. Irrespective of appearance, the lesions occur predominantly in areas exposed to the sun on the upper part of the body and rarely affect on the inner arms, sides or armpits. Subacute lupus lesions develop separately from other systemic disease manifestations and require specific management by a dermatologist. The lesions generally regress without leaving scars, but may sometimes leave the skin temporarily more or less pigmented. Subacute lupus is associated with the presence of anti-Ro/SS-A antibodies. The appearance of lesions is sometimes triggered by the administration of a medicinal product.
CHRONIC LUPUS ERYTHEMATOSUS LESIONS
Chronic lupus erythematosus includes four entities: discoid lupus erythematosus, lupus tumidus, chilblain lupus erythematosus and lupus erythematosus panniculitis.
Discoid lupus erythematosus
Frequently, discoid lupus gives rise to isolated lesions with no internal organ involvement. The lesions form well delimited plaques and present the following three characteristics: erythematous or red patches with well-defined borders covered with fine telangiectasias (visible superficial blood vessels), thick scales that plug the follicular orifices and atrophy or thinning of the skin which gives rise to scars mainly in the centre of the lesions. Patients often present with numerous lesions, predominantly on the face, sometimes in the shape of a butterfly which may lead to them being confused with the lesions of acute lupus erythematosus. The lesions are also typically found on the ears, the eyebrows and scalp. On regression, scalp plaques give rise to scarring alopecia similar to that observed with pseudo-pelade. The hair loss is definitive and the scalp takes on a new appearance. The lesions of discoid lupus evolve differently to the lesions of systemic lupus erythematosus and leave very unsightly definitive scars, which makes it essential for patients to be rapidly taken in hand by a specialist. Discoid lupus erythematosus may also occur in the disseminated form with lesions appearing on the chest and limbs. Disseminated discoid lupus lesions occur predominantly on the elbows and extremities. Palmar-plantar lesions are common and particularly disabling as they cause much pain and are often resistant to treatment. The palmar lesions make all manual activities impossible while the plantar lesions make walking very difficult.
The lesions of lupus tumidus present as multiple infiltrated plaques without scales or crusts. They are violet-red in colour and call to mind a specific type of urticaria that gives rise to fixed lesions. There is no risk of thinning of the cicatricial skin. Some lesions may have a central depression. The lesions occur mainly on the face and on the sun-exposed parts of the upper body. The lesions generally disappear without leaving any scars.
Clinically, chilbain lupus lesions present as common chilblains but they persist even when the weather gets warmer. They most often occur on the fingers and toes, but may also be observed on the ears, nose, calves, heels, elbows and knees.
Lupus erythematosus panniculitis (or lupus erythematosus profundus)
Lupus erythematosus panniculitis starts as infiltrated erythematous nodules of variable size. The skin covering the nodules sometimes presents discoid lupus lesions. On regression, the lesions leave a characteristic cup-shaped depression enabling retrospective diagnosis of the condition. The lesions generally occur on the upper third of the arms, the cheeks, the thighs and the breasts.
Various types of cutaneous lupus lesions may occur together in one patient. The most commonly occurring combinations are subacute lupus/discoid lupus and discoid lupus/Lupus erythematosus panniculitis. If there are any uncertainties about the lesion type, a skin biopsy should be performed and the sample examined by direct immunofluorescence.
All the forms of cutaneous lupus may be associated with systemic lupus with the degree of association varying as a function of the type of cutaneous lupus. Fifty per cent of patients presenting with subacute lupus have also suffered from or will suffer from systemic lupus (separately) against 10 to 20% of patients presenting with chronic lupus. To date, no formal predictive factor of the risk of evolution into systemic lupus have been has been isolated but several paths have been explored. The risk seems to be higher with disseminated forms compared to localised forms and in women in whom lesions worsen during the premenstrual period or pregnancy.
CUTANEOUS LUPUS AND SMOKING
A study has shown that the proportion of smokers presenting with cutaneous lupus is greater than that compared to patients who consult for other dermatological diseases (73% against 49%), and the rates are even higher in men presenting with discoid lupus (>80%). Moreover, it has been shown that the cutaneous lupus lesions of smokers are less sensitive to treatment, particularly treatment with hydroxychloroquine (Plaquenil®), than the lesions of non-smokers but no scientific explanations have yet been put forward. Hydroxychloroquine blood levels are comparable in smokers and non-smokers, which excludes a metabolic cause related to smoking and refractory cutaneous lupus lesions are also resistant to many treatments other than hydroxychloroquine. Other hypotheses are also being studied, i.e. a direct effect of smoking on the skin or a genetic makeup predisposing subjects to refractory cutaneous lupus and intoxication from cigarette smoking. Some patients reported that their lesions improved significantly when they stopped smoking and reappeared when they started smoking again while others noted no change. Taking into consideration current knowledge and given that lesions may potentially be improved by smoking discontinuation, physicians should insist on patients stopping smoking and make every effort to help them stop.
MANAGEMENT OF SUBACUTE AND CHRONIC LUPUS LESIONS
Sun protective measures are the first measures that should be implemented for all cutaneous lupus lesions. The best way for patients to protect themselves from the sun is to wear protective clothing, i.e. long pants, long-sleeved shirts and hats. However, in order for patients to lead lives as normal as possible, use of broad spectrum sunscreen (UVA, UVB and visible light) with a high protective index (SFP > 50) is indispensible on the sun-exposed areas of the body. Women are advised to wear makeup (essentially foundation and powder) in addition to sunscreen as it provides additional protection and masks the lesions.
Application of topical dermocorticosteroids and/or topical immunesuppressants sometimes suffices for the treatment of localised forms of the disease. Dermocorticosteroids give rise to skin atrophy after prolonged use which means treatment should be limited in time, particularly for facial lesions. The risk of atrophy is less of a nuisance for the scalp. Tacrolimus is a topical calcineurin inhibitor immunomodulator (Protopic®) that does not cause cutaneous atrophy. In a double blind study of the various forms of cutaneous lupus, it was found to be particularly effective for the treatment of lupus tumidus lesions, to have a more moderate effect on subacute lupus and very little effect on discoid lupus lesions. The efficacy of pimecrolimus, an immunomodulater of the same family (Elidel®) not yet commercially available in France, has been found to be similar.
Patients with more widespread cutaneous lupus lesions or with lesions resistant to topical treatment often require systemic treatment. Patients should not be treated with systemic corticosteroids. As oral corticosteroids are only mildly effective, they need to be administered at high doses incompatible with the long-term therapy required by patients with subacute or chronic lesions.
Synthetic antimalarials are the first line treatments of choice for cutaneous lupus, particularly hydroxychloroquine (Plaquenil®) at the dose of 6.5 mg/kg/d and chloroquine (Nivaquine®) at the dose of 4 mg/kg/d. Hydroxychloroquine should be used first-line as it gives rise to fewer side effects, particularly fewer ocular effects (retinopathy), than chloroquine. Ocular toxicity is one of the serious but fortunately rare concerns associated with this class of drugs. A net improvement of skin lesions is observed in 50-80% of patients, but only after 3 months of treatment. The pharmacodynamics and mechanisms of action of the molecules on cutaneous lupus lesions have not been completely elucidated. An ophthalmological assessment is recommended at the start of treatment or in the first few months of treatment to screen for any potential pre-existing abnormalities. The assessment should include a standard ophthalmological exam and at least two other specialised tests like an automated visual field test and a multifocal electroretinogram (mfERG). The multifocal electroretinogram may be replaced by one of the following two tests which are not commonly conducted in France, i.e. spectral domain optical coherence tomography (SD-OCT) or fundus autofluorescence (FAF) imaging.
In the absence of factors that could lead to potential toxicity (elevated daily dose, elderly subject, prior ocular disease, hepatic or renal disorders), these tests need only to be repeated every year after five years of treatment . Hydroxychloroquine is not contraindicated during pregnancy. On the contrary, it limits systemic lupus flare-ups and does not have teratogenic effect. HCQ may give rise to skin pigmentations after several years of treatment. The pigmented lesions occur predominantly on the legs, but may also be observed on the mucosal tissues, i.e. the palate, and on the nails. The pigmented lesions are a non-serious side effect and do not call for treatment to be discontinued. The other cutaneous adverse effects associated with antimalarials are aquagenic urticaria (skin reaction resulting from contact with water) and rarely, generalised rash which is an allergic reaction that requires specific investigation and management.
Approximately 20%-50% of cutaneous lupus lesions do not respond to treatment with hydroxychloroquine. Before concluding that the first-line treatment has failed, hydroxychloroquine blood levels need to be assayed to determine the patient’s compliance with treatment. A national, prospective multicentre study including 300 patients treated with hydroxychloroquine for cutaneous lupus found that the hydroxychloroquine blood levels of 10% of the subjects were too low to be compatible with regular taking of treatment. It is not recommended to switch these patients to more aggressive and more toxic second-line treatment. Above all, they need therapeutic education to learn how to better comply with treatment. The value of adapting the daily dose of hydroxychloroquine as a function of blood levels is currently under study.
Patients with normal hydroxychloroquine blood levels presenting with treatment-resistant lesions may be treated with nivaquine for 3 months bearing in mind that approximately 7 to 10% of patients resistant to hydroxychloroquine are sensitive to chloroquine. Other treatment regimens combining various antimalarials are proposed in other European countries and in the United States, chloroquine or hydroxychloroquine is combined with quinacrine. Quinacrine is another synthetic antimalarial far less likely to cause ocular effects. Unfortunately, it is not commercialised in France and is therefore not prescribed very often given its lack of availability.
Thalidomide is an immunomodulator that has been available since the 50s. It was first used for its anti-nausea effects. It is often used for the second line treatment of cutaneous lupus in France at a starting dose of 100 mg/d. It generally produces results very rapidly with refractory skin lesions disappearing in less than two months. Patients need to be given lower so-called maintenance doses for long periods as relapses are common when treatment is discontinued. This molecule gives rise to many more adverse effects than the antimalarials. It notably has a teratogenic effect (induces foetal malformations if taken during pregnancy). It is also associated with peripheral sensory neuropathy (tingling or numbness of the arms, hands, legs and/or feet), somnolence, weight gain and menstrual disorders. As it is also associated with a risk of thrombosis, thalidomide needs to be taken with small, thrombosis-preventing doses of aspirin (100 mg/d or baby aspirin). The rules for prescribing thalidomide are very strict in France: it has to be prescribed by a duly authorized physician and it is only distributed in hospitals. Patients must give their written consent and women of childbearing potential must undergo a monthly pregnancy test and men are forbidden to procreate.
There is no codified third-line treatment strategy if thalidomide fails or is contraindicated. Several molecules have been proposed and studied with variable results depending on the subjects. The treatment strategy must be implemented after determining the benefit/risk ratio for each product as a function of each individual patient.
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