CME-Article Submitted: 7.8.2013 Accepted: 12.10.2013 Conflict of interest None.

DOI: 10.1111/ddg.12254

Lupus erythematosus. Part II: Clinical picture, diagnosis and treatment

Mirjana Ziemer, Linda Milkova, Manfred Kunz Department of Dermatology, ­Venereology and Allergology, ­University of Leipzig, Leipzig, Germany Section Editor Prof. Dr. Jan C. Simon, Leipzig

Summary Lupus erythematosus (LE) is an important dermatologic autoimmune disease. In many respects, it may be regarded as a model autoimmune disease due to its spectrum of autoimmune antibodies and involvement of different organ systems, as well as response to immunosuppressive agents which target B cells and T cells and their cytokines. A recently published article in this Journal summarized the most important knowledge about epidemiology, genetics, and immunology of LE. Here, the different clinical manifestations, diagnostic procedures and current therapeutic approaches will be described. Special emphasis is placed on different cutaneous manifestations of LE. In regard to treatment, the classic treatment approaches such as corticosteroids, methotrexate, chloroquine and hydroxychloroquine will be described. Lastly, new therapeutic approaches with specific monoclonal antibodies which are currently used in systemic LE, such as belimumab (Benlysta®), will be addressed. The most recent developments in this area could have implications even for purely cutaneous forms of LE.

Introduction Lupus erythematosus (LE) is a systemic ­autoimmune disease with variable clinical symptoms which range from mild cutaneous involvement to life-threatening visceral manifestations. LE can manifest in any organ system. The majority of ­patients have cutaneous involvement.

Lupus erythematosus (LE) is a systemic autoimmune disease with variable clinical symptoms which range from mild cutaneous involvement to life-threatening ­visceral manifestations. LE can manifest in any organ system. The majority of patients have cutaneous involvement. In recent years there have been advancements in terms of the clinical classification, diagnosis, and treatment which are relevant to the treatment of patients with LE. The following presents the most important of these.

Clinical appearance It is advisable to first classify the LE-specific skin changes based on their morphology. A classification of variants has been suggested by Gilliam and Sontheimer: chronic cutaneous LE (CCLE) with discoid LE (DLE), chilblain LE, tumid LE, and lupus profundus, subacute cutaneous LE (SCLE), and acute cutaneous LE (ACLE).

Classification It is advisable to first classify the LE-specific skin changes based on their morphology. Using the classification of variants suggested by Gilliam and Sontheimer, they may be divided as follows: chronic cutaneous LE (CCLE) with discoid LE (DLE), chilblain LE, tumid LE, and lupus profundus, subacute cutaneous LE (SCLE), and acute cutaneous LE (ACLE). [1]. Lupus tumidus has recently been described as a separate entity and referred to as intermittent LE. All of these terms should be reserved for the morphological interpretation of skin changes. Occasionally, it is

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The clinical/morphological assessment of skin changes is complemented by a histopathological examination. It is usually impossible to classify individual sub-types based solely by their histology; clinical/ histological c­ orrelation is necessary. The possibility and extent of systemic involvement may be determined using additional diagnostic tests such as laboratory studies or other methods.

Certain cutaneous manifestations are more or less often associated with extracutaneous organ manifestation. In localized DLE, extracutaneous involvement is less common; the reverse is true in patients with disseminated DLE or papulosquamous SCLE, who are more likely to have SLE.

The ACR criteria were recently revised by the Systemic Lupus International Collaborating Clinics (SLICC). A total of 17 clinical and immunological criteria were established which have greater specificity and sensitivity than the previously used ACR criteria.

nearly impossible to distinguish localized ACLE from papulosquamous SCLE, or DLE from SCLE, purely by clinical appearance (Table 1). The clinical/morphological assessment of skin changes is complemented by a histopathological examination. It is usually impossible to classify individual sub-types based solely by their histology; clinical/histological correlation is necessary. The extent of possible systemic involvement may be determined by using additional diagnostic tests such as laboratory tests or other methods. Next, lupus that is limited to the skin, or cutaneous LE (CLE) should be distinguished from intermediate LE with mild systemic involvement or SLE. Intermediate LE is a mild form of systemic disease; patients do not meet the ACR criteria for SLE [2]. A two-dimensional classification system (Table 2) [3] was recently proposed by a Japanese group based on the manifestation types of cutaneous lupus and the diagnostic terms (CLE, intermediate LE, and SLE) for the symptoms. Certain cutaneous manifestations are more or less often associated with extracutaneous organ manifestation. In localized DLE, extracutaneous involvement is less common; the reverse is true in patients with disseminated DLE or papulosquamous SCLE, who are more likely to have SLE. About 80 % of SLE patients have specific skin changes; the commonly used ACR criteria for confirming SLE place great importance on relatively unspecific skin changes, such as butterfly rash, discoid lesions, oral and nasal mucosal ulcers, and photosensitivity. In many patients with isolated cutaneous manifestation, the mere presence of skin symptoms may thus fulfill the required four ACR [2] (Table 1). A butterfly rash can be observed in conjunction with various cutaneous manifestation forms of LE (Table 3). The ACR criteria for the diagnosis of SLE have been the subject of increasing criticism. To establish a diagnosis, LE-unspecific cutaneous manifestations, which are commonly associated with SLE, are also often used. These include periungual ­telangiectasias, livedo racemosa, thrombophlebitis, and Raynaud syndrome. The European Academy of Dermatology and Venereology (EADV) has suggested criteria for determining SLE which include the ACR criteria for LE-unspecific cutaneous manifestations and additional parameters: muscle weakness, lupus band test, ESR, anti-Ro/SSA and anti-La/SSB antibodies. Their specificity is high (93 %), but their sensitivity is low (64 %) [5]. The ACR criteria were recently revised by the Systemic Lupus International Collaborating Clinics (SLICC). A total of 17 clinical and immunological criteria were established which have greater sensitivity and specificity than the previously used ACR criteria [6].

Morphological spectrum of the skin manifestations

Epidermodermal variants (e.g., SCLE and DLE) may be distinguished from primarily dermal (lupus tumidus) and subcutaneous forms (lupus panniculitis). Yet, epidermal, dermal, and subcutaneous changes often overlap.

In terms of clinical/morphological appearance, LE encompasses a wide variety of cutaneous manifestations. Their severity depends on a number of factors, including genetic and immunological aspects, as well as disease stage. Certain LE subtypes are easily defined by their characteristic clinical, histopathological, immunological, and genetic appearances. Yet, quite often, the exact classification is difficult (Table 1). Epidermodermal variants (e.g., SCLE and DLE) may be distinguished from primarily dermal (lupus tumidus) and subcutaneous forms (lupus panniculitis). Yet, epidermal, dermal, and subcutaneous changes often overlap (Tables 1, 4).

Epidermodermal variants SCLE and DLE are the most common variants of cutaneous LE.

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SCLE and DLE are the most common variants of cutaneous LE. The clinical characteristics, including ACLE, are listed in Table 5. Specific manifestations of SCLE

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Laboratory results

Clinical ­appearance

ANA ∅ ANA ⊕ 1 : 320 Ro/SSA, La/SSB antibodies ∅ Ro/SSA antibodies ⊕

ANA ⊕ 1 : 640 Ro/SSA-AK ⊕, ds DNA-AK ⊕, nucleosomes antibodies ⊕

ANA ⊕ 1 : 320 Ro/SSA, La/SSB antibodies ⊕

ANA ⊕ 1 : 5 120 Ro/SSA, La/SSB antibodies ⊕

Table 1  Erythematosquamous plaques in patients with lupus erythematosus of different clinical variations with corresponding histology and laboratory parameters.

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Diagnosis

Histology

CDLE in limited cutaneous LE

Table 1  Continued.

SCLE in intermediate LE

SCLE in SLE

SCLE, REM and lupus ­tumidus in intermediate LE

SCLE / ACLE in intermediate LE

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CME Article  Lupus erythematosus

Table 2  Suggestion of a two-dimensional classification system of lupus erythematosus (after Tsuchida et al. [3]). Systemic Manifestations

Cutaneous manifestations

Limited cutaneous LE

Intermediate LE

Systemic LE

CCLE (chronic cutaneous LE)

 

 

 

Discoid LE

localized

 

 

 

disseminated

 

 

 

Chilblain LE

 

 

Lupus tumidus

 

 

Lupus profundus/panniculitis

   

  SCLE (subacute cutaneous LE)

 

 

 

Annular

 

 

 

Papulosquamous

 

 

 

 

 

 

  ACLE (acute cutaneous LE)

- Predominance of individual morphological manifestation forms

and ACLE, which resemble erythema multiforme, are known as Rowell syndrome. Variants of SCLE and ACLE, which resemble Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) in terms of clinical and histological symptoms, are described as SJS or TEN-like LE; these must be distinguished, if possible, from a severe skin reaction based on the clinical features and the patient history [7]. Bullous LE is another form which usually develops acutely in SLE with subepidermal collections of neutrophilic granulocytes and subsequent subepidermal blistering.

Dermal variants Among the manifestation forms of LE with pronounced dermal involvement are lupus tumidus and chilblain lupus (Tables 4, 6). In many instances, lymphocytic infiltration (Jessner-Kanof) and reticular erythematous mucinous (REM) may also be classified as tumid LE.

Subcutaneous lupus erythematosus Lupus erythematosus profundus and lupus panniculitis usually manifest in the subcutaneous fatty tissue (Tables 4, 7).

The histological evaluation of skin changes is key to diagnosing LE. LE has a broad spectrum of histopathological changes which depend on the stage of development of the lesions and the disease.

Diagnosis Histopathology The histological evaluation of skin changes is key to diagnosing LE, which has a broad spectrum of histopathological changes which depend on the stage of

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Table 3  Centrofacial erythema (butterfly rash) in different clinical manifestations of lupus erythematosus with corresponding histology.

Woman with SCLE in intermediate LE

Woman with ACLE in SLE

Woman with CDLE in SLE

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Table 4  Subcutaneous involvement in different clinical manifestations of lupus erythematosus and corresponding histology.

Lupus profundus in limited cutaneous LE

CDLE with subcutaneous involvement in limited cutaneous LE

Lupus tumidus with subcutaneous involvement in limited cutaneous LE

From a histopathological standpoint, LE may be divided into early disease, ­full-blown disease, and late-onset lupus, or into specific manifestations (bullous LE).

­ evelopment of the lesions and the disease (Table 8). There is significant overlap d between the various clinical subtypes of LE. A purely histological classification is impossible, and thus the clinical/histopathological correlation is crucial. From a histopathological standpoint, LE may be divided into an early disease, full-blown disease, and late-onset lupus or into specific manifestations (bullous LE) [8]. Full-blown discoid lupus involves the most histopathological changes and thus may be considered a histopathological model [9].

Lupus band test Direct immunofluorescence (DIF) testing is an additional histopathological method of examination. Often, immunoglobulin deposits (IgG, IgM) and complement deposits (C3c) are found along the basement membrane zone. The diagnostic criteria

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  E xtracutaneous manifestations in 60–70 % such

as joint complaints, nephropathy, fever, myalgia, Raynaud phenomenon   In ca. 15 % in the framework of SLE   Possible antibody transmission through the placenta, triggering congenital SCLE and AV block

  Favorable prognosis quoad vitam

  O ften long-term active skin changes

  Cosmetically disturbing scarring

Prognosis / ­Outcome

­ ermatomyositis, cutaneous T-cell ­lymphoma, d drug eruption

  T inea, psoriasis, nummular eczema,

occurring in SLE

  At 30–60 % the most common type

multiforme, toxic epidermal necrolysis, Still syndrome

  V iral and drug eruption, e ­ rythema

*Follicular keratosis is rare in DLE. # Butterfly rash may occur in various manifestation forms of LE. It appears as a persistent centrofacial slightly urticarial erythema (ACLE in patients with SLE), but may also occur as an initial erythema in SCLE and DLE patients (see also Table 3). It may also occur in other disorders, such as rosacea.

  In 10% DLE first sign of SLE

  E xtracutaneous manifestations in 14–27 %

  Generally mild course

  T inea faciei, lupus vulgaris, sarcoidosis

Differential ­diagnosis

  Rheumatoid factor in 30 %

­ds-DNA and in 10–30 % against Sm

  in 40–90 % antibodies against

  Anti-Ro/SSA antibodies in 70–90 %   Anti-La/SSB antibodies in 30–50 %

  Generally high titer ANA

  Positive ANA in up to 90 %

  Low titer ANA in 20–30 %, high titer ANA is rare

  Enanthem and isolated erosions

Paraclinical ­changes

  Usually none

   Generalized exanthema    Centrofacial butterfly rash#   “Bullous LE”   Heals without scarring

  Maculopapular exanthema

(mainly hard palate, less often ­gingiva, buccal or nasal mucosa)   Also on vermillion border

  isolated, slight erosions

   Annular configuration    No annular configuration   Healing without scarring but often with

   Localized on skin that is exposed to sunlight    Disseminated   Mainly follicular dilatations with hyperkeratosis*   Healing with atrophy   Possible Koebner phenomenon ­diminished or loss of pigmentation

  Erythematosquamous papules/plaques

  Erythematosquamous papules/plaques

Acute cutaneous lupus ­erythematosus (ACLE)

  discoid lesions on the vermillion border

Mucosal changes

Skin changes

Subacute cutaneous lupus erythematosus (SCLE)

Discoid lupus erythematosus (DLE)

Table 5  Clinical characteristics of predominantly epidermodermal variants of lupus erythematosus.

CME Article  Lupus erythematosus

CME Article  Lupus erythematosus

Table 6  Clinical characteristics of dermal variants of lupus erythematosus.

Skin changes

Lupus tumidus

Chilblain LE

  Erythematous, urticarial, arciform

  Bright-red, swollen nodules, some with firmly

­ laques on the face, upper e p ­ xtremities, and trunk

­ ttached keratoses on the dorsal aspects of the a ­f ingers, toes, nose, ears, elbows, knees, and heels

Mucosal changes

  None

  None

Paraclinical changes

  Positive ANA in 10–30 %

  Positive ANA 50–60 %   O ften cryoglobulinemia   Variable with anti-Ro/SSA and anti-La/SSB antibodies

Differential diagnosis

  Polymorphous light eruption, cutaneous

Prognosis / Outcome

  Favorable

  Perniones, sarcoidosis (lupus pernio), acral vasculitis

B-cell lymphoma, pseudolymphoma (incl. Borrelia-associated)   In ca. 20 % in the framework of SLE

  Spontaneous regression is possible

Table 7  Clinical characteristics of subcutaneous lupus erythematosus. Lupus erythematosus profundus/lupus panniculitis Skin changes

  Subcutaneous with superficial hard nodules or infiltrates mainly on gluteal regions,

thighs, and upper arms   In acute stages with inflammation of adjacent skin   Healing with scarring and lipoatrophy   Koebner phenomenon may occur   O ften associated with DLE

Mucosal changes

  None

Extracutaneous symptoms

  O ften mild systemic changes with arthralgia, Raynaud syndrome, thrombophlebitis

Paraclinical changes

  Positive ANA in up to 50 %

Differential diagnosis

  Subcutaneous sarcoidosis, malignant lymphoma

Prognosis/Outcome

  Atrophic scarring

The significance of DIF in diagnosing LE is no longer as valued as it previously was.

have not been clearly defined, however, which complicates the assessment; specificity is also inadequate, and the assessments of findings differs. Specimens lack uniformity, given that they are taken from lesions of various ages, and from different regions within the lesions themselves – sometimes from the margin and sometimes from the center – causing a great deal of variation in the detection of immunoglobulin deposition. The likelihood of positive results in lesional skin ranges from 50– 90 %. Fine, granular, band-like deposits as well as plaque-like IgG deposits have been described along the dermoepidermal junction zone. Compared to examining only isolated IgG deposits, the specificity seems higher if several immunoglobulins and complement are studied. DIF is routinely performed on biopsies taken from areas of the skin with little exposure to the sun to rule out SLE; in SLE, the results are 80 % positive. In isolated cutaneous manifestations, the lupus band test is usually negative on unaffected skin, and is nowadays no longer considered necessary. The significance of DIF in diagnosing LE is no longer as valued as it previously was.

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Table 8  Histopathologic spectrum of cutaneous lupus erythematosus (adapted after Ackerman et al.[8]) Early cutaneous LE

Full-blown cutaneous LE

Late-onset cutaneous LE

  Focal

vacuolar ­ egeneration along the d dermoepidermal junction zone   Few individual necrotic ­keratinocytes

  Focal or continuous epidermal atrophy

  Epidermal atrophy with loss

Dermal ­changes

  Scant

superficial perivascular lymphocytic infiltrate   Occasionally neutrophils and nuclear debris along the dermoepidermal ­junction zone   Some interstitial mucin deposits in the reticular dermis

  Moderate

to dense superficial and deep perivascular and periadnexal lymphocytic infiltrate   Melanophages in the papillary dermis   Abundant interstitial mucin deposits in the reticular dermis

  Residual,

Subcutaneous changes

  Lobular panniculitis with

  lobular panniculitis with dense

  Residual lobular ­lymphocytic

­lymphocytic infiltrate   Fatty tissue necrosis

  Fibrosis and/or hyalinization

Epidermal ­changes

lymphocytic infiltrate

(in CDLE alternating acanthotic areas)   Vacuolar degeneration along the ­dermoepidermal junction zone   Individual necrotic keratinocytes   Thickening of basement membrane   Compact orthokeratosis   Follicular keratin plugs

of rete ridges vacuolar degeneration along the dermoepidermal junction zone   Thickened basement ­membrane   Follicular atrophy   Residual

superficial, perivascular lymphocytic infiltrate   Residual melanophages in the papillary dermis   O ften interstitial mucin ­deposits in the reticular dermis   Dermal fibrosclerosis

panniculitis of fatty tissue

Laboratory diagnosis In regard to laboratory diagnosis, the identification of antinuclear antibodies (ANA) in serum is especially important. High titer is defined as ≥ 1: 320. The detection of high titer levels varies by subtype.

In addition to ANA titers, the complement factors C3 and C4, antiphospholipid antibodies, rheumatoid factor, urine status, 24-hour urine protein, CBC with differential, liver enzymes, and renal function should be examined.

In regard to laboratory diagnosis, the identification of antinuclear antibodies (ANA) in serum is especially important. High titer is defined as ≥ 1: 320. The detection of high titer levels varies by subtype. A recently published study on more than 1,000 patients examined the frequency of increased ANA titer levels [10]. Elevated ANA titers were found in more than 90 % of patients with 4 or more ACR criteria and in nearly 50 % of patients with less than 4 ACR criteria. More than 30 % in the first group had positive anti-ds (double-stranded) DNA antibodies compared with nearly 5 % in the second group. Anti-Ro/SSA antibodies were found in more than two-thirds of patients with SCLE, but in only one-fifth of patients with CCLE. Anti-La/SSB antibodies were found in one-third of patients with SCLE and in fewer than 10 % with CCLE. Anti-ds DNA antibodies were mainly identified in ACLE patients (about one-third). In addition to ANA titers, the complement factors C3 and C4, antiphospholipid antibodies, rheumatoid factor, urine status, 24-hour urine protein, CBC with differential, liver enzymes, and renal function should be examined. Other specific blood tests depend on the selected treatment. For instance, depending on predisposing factors, glucose-6-phosphate dehydrogenase activity may need to be evaluated before starting classic treatment with antimalarial drugs; it should routinely be assessed before planned dapsone therapy.

Photodiagnosis Lupus erythematosus may be provoked by exposure to UV light.

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Lupus erythematosus may be provoked by exposure to UV light, and many patients report photosensitivity and the appearance of LE lesions after exposure the UV light.

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CME Article  Lupus erythematosus

Standardized protocols are available for provoking cutaneous LE lesions with UV light [11]. UVA light (depending on skin type 60–100 J/cm2) and UVB light (1.5 times the minimal erythema dose, which should be determined beforehand) should be used. Exposure should be on three consecutive days, and the test field should be an area of skin without chronic sun exposure. The readings are done after 24, 48, and 72 hours, and then for up to 3 weeks. The skin changes occurring during this time should be biopsied if necessary to confirm the diagnosis of cutaneous LE. Larger studies have shown that LE lesions occur after nearly 7 days on average and have a latency period three times longer than changes provoked in patients with polymorphous light eruption. About 60 % of patients with cutaneous LE may be expected to have a positive reaction. The patient history has no predictive value in terms of photoprovocation. Slightly less than 70 % of patients with a positive history of photosensitivity actually respond positively to photoprovocation, while 50 % of patients with a negative history test positive. Intermittent CLE is the most photosensitive variant (74.8 %). SCLE patients react significantly more often (two-thirds of affected patients) than CCLE patients. Occasionally, over the course of several tests, patients who had a positive reaction no longer have one, or patients who tested negative are suddenly positive.

Therapy At present, there are no approved drugs for systemic CLE therapy; for SLE, there are only a few.

At present, there are no approved drugs for systemic CLE therapy; for SLE, there are only a few. Treatment should be tailored to the individual patient, taking into account the effect/side effect profile of the preparation, the cost-benefit ratio, and the patient's wishes. For treatment of CLE, the reader is referred to the current S1 guidelines (http://www.awmf.org/leitlinien/aktuelle-leitlinien.html).

Prevention Effective UV protection is essential. Chemical or physical sunscreens (SPF 50+, dosage 2 mg/cm2 of body surface area; UVA and UVB protection) should be used, and protective clothing worn.

Medication use is the cause of disease in about 6 % of CLE patients and up to 10 % of SLE patients.

Due to activation of inflammatory processes, ultraviolet radiation leads to autoantigen presentation and thus to initiation and maintenance of disease activity. Various studies have shown an association between skin changes and UVA and UVB irradiation. Effective UV protection is thus essential. Chemical or physical sunscreens (SPF 50+, dosage 2 mg/cm 2 of body surface area; UVA and UVB protection) should be used, and protective clothing worn. Patients should avoid sunny areas and solarium use. Nicotine consumption is another factor triggering disease. Patients should be advised to stop smoking, not least due to the fact that it reduces the effectiveness of treatment with antimalarial drugs [12]. Medication use is the cause of disease in about 6 % of CLE patients and up to 10 % of SLE patients [13]. Possible triggering drugs, including ACE inhibitors, antiepileptic drugs, blood pressure medication, statins, anti-inflammatory drugs, antifungals, and biologicals, should be discontinued. If necessary, they should be replaced by other drugs. Patients should be aware of the Köbner phenomenon and avoid trauma.

Topical therapy Topical class II and III corticosteroids (prednicarbate, mometasone furoate, methylprednisolone aceponate) are an important part of treating cutaneous manifestations of LE.

Topical class II and III corticosteroids (prednicarbate, mometasone furoate, methylprednisolone aceponate) are an important part of treating cutaneous manifestations of LE. Class IV corticosteroids may be applied to the scalp, palms, and plantar regions. They may also be applied to hyperkeratotic areas, if needed under occlusion using hydrocolloid dressings. Topical corticosteroids have been

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To avoid side effects of topical corticosteroids, the off-label use of calcineurin inhibitors is increasing.

shown to effectively reduce the inflammatory activity in LE lesions, although this is supported by only one randomized controlled study. When administering topical steroids, known side effects such as atrophy and telangiectasias should be taken into account, which prevents their long-term use on the face and intertriginous zones. Intralesional injection of triamcinolone acetonide (0.1–0.2 ml in a suspension of 10 mg/ml) may occasionally be suitable for DLE patients. Given the risk of lipoatrophy, strict intradermal administration should be ensured. To avoid side effects of topical corticosteroids, the off-label use of calcineurin inhibitors is increasing. These drugs inhibit calcineurin-mediated formation of numerous inflammatory mediators. The results of a randomized double-blind study found no significant difference between the effectiveness of 0.05 % clobetasol propionate and 0.1 % tacrolimus ointment. Several small, and generally uncontrolled, studies have been conducted, sometimes with contradictory results [14]. Their use is warranted in inflammatory types of CLE and in SCLE; they may also be used on the face and in intertriginous zones due to the risk of atrophy and telangiectasias. Drugs used for further treatment of CLE include the topical preparations R-salbutamol, which is a β2-sympathomimetic that has been used to treat bronchial asthma [15]. Physical treatments, including pulsed dye laser, argon or carbon dioxide laser, cryotherapy, and dermabrasion, should be performed in conjunction with antimalarial treatment, given the risk of the Koebner phenomenon [14].

Systemic therapy In general, in advanced disease, systemic immunomodulatory drugs or immunosuppressants are indicated. The increased risk of opportunistic infections should be taken into account. Before beginning immunosuppressant treatment, pre-existing HIV infection, hepatitis B and C, as well as tuberculosis should be ruled out. Patients who are taking immunosuppressants should promptly consult their physician if signs of infection develop. Patients with systemic manifestations of LE, including arthralgia, cephalgia, and myalgia, should be given non-steroidal anti-inflammatory drugs to treat their symptoms. Administration of Voltaren 50–150 mg/daily or aspirin may be wise. LE has also been shown to be associated with hormonal factors. Patients should avoid taking estrogen; women who are using oral contraceptives should take one that contains mostly progesterone.

Systemic corticosteroids Systemic corticosteroids are mainly indicated during acute flare-ups or while waiting for an antimalarial drug to take effect. Corticosteroids are an important part of treatment in SLE patients.

Systemic corticosteroids are mainly indicated during acute flare-ups or while waiting for an antimalarial drug to take effect. Patients with CLE should be given 0.5 to 2 mg/kg/daily for 2 to 4 weeks [14, 16]. Corticosteroids are an important part of treatment in SLE patients [17]. For long-term control of SLE, systemic steroids (5–20 mg prednisolone equivalent daily) are often unavoidable. Still, non-steroidal immunosuppressants should be started as soon as possible. Side effects include Cushing syndrome, arterial hypertension, hyperglycemia, osteoporosis, and increased intraocular pressure. Proton pump inhibitors should be given to protect the gastric mucosa, and calcium and vitamin D to prevent osteoporosis (1–1.5 g/ daily or 400–800 IU/daily).

Antimalarial drugs Since 1953, treatment of cutaneous LE has consisted of administration of antimalarial drugs such as chloroquine and hydroxychloroquine (HCQ) and mepacrine

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Since 1953, treatment of cutaneous LE has consisted of administration of ­antimalarial drugs such as chloroquine and hydroxychloroquine (HCQ) and mepacrine (not approved for use in Germany). They are effective in 50– 80% or more of patients, and are thus considered the first-line treatment.

The dosage is based on ideal body weight.

In patients with SLE, antimalarial drugs alone are usually unable to achieve effective disease control, yet they are an important part of treatment. ­Administration of HCQ also helps to ­reduce steroid use.

(not approved for use in Germany). They are effective in 50–80 % or more of patients, and are thus considered the first-line treatment [12, 18]. The mode of action of these substances has not been fully explained, although their effect is presumably due to immunomodulatory effects, such as influencing antigen presentation, stabilizing lysosomes, and suppression of the toll-like-receptor signal transduction pathway (especially TLR9) [12]. Hydroxychloroquine is preferred over chloroquine due to its better tolerability. Blood changes and gastrointestinal symptoms may occasionally occur. Especially in patients from Mediterranean regions and tropical/subtropical regions, before beginning treatment, it may be advisable to measure glucose-6-phosphate dehydrogenase activity. Due to rare (< 1 : 1 000), but irreversible retinopathy, regular ophthalmological controls should be performed before therapy and every 12 months during it (or more often in patients who are over age 50 or have liver or renal insufficiency). The dosage is based on ideal body weight. The recommended dosage of chloroquine is 3.5–4 mg/kg of ideal body weight; for hydroxychloroquine, it is 6.0–6.5 mg/kg of ideal body weight. For low-weight patients, the patient's actual weight should be used to calculate the dosage. If there is no improvement within 3–6 months, combination treatment with mepacrine (100 mg/daily) should be considered. Side effects include gastrointestinal complaints and yellow discoloration of the skin and mucous membranes. If treatment is still ineffective after another three months, it should be considered ineffective and discontinued. In patients with SLE, antimalarial drugs alone are usually unable to achieve effective disease control, yet they are an important part of treatment. Administration of HCQ also helps to reduce steroid use [19].

Methotrexate (MTX) MTX was first used in 1965 to treat SLE. We now have many years of experience in its use, showing it to be highly ­effective (comparable to chloroquine) especially in DLE and SCLE. A dosage of 7.5 mg to 25 mg (0.2 mg/kg of body weight) should be given once per week. Medication may be taken orally, intravenously, or subcutaneously.

MTX inhibits the enzyme dihydrofolate reductase and thus T-cell proliferation. MTX was first used in 1965 to treat SLE [20]. We now have many years of experience in its use, showing it to be highly effective (comparable to chloroquine) especially in DLE and SCLE [21, 22]. Miyawaki and colleagues reported that MTX led to a significant reduction in autoantibodies (92.3 %) compared to a control group (50 %) [23]. A dosage of 7.5 mg to 25 mg (0.2 mg/kg of body weight) should be given once per week. Medication may be taken orally, intravenously, or subcutaneously. Subcutaneous administration is preferable, given its better tolerability. Folic acid substitution, e.g., with 5 mg folic acid, should be given on the next day. Side effects include gastrointestinal complaints, hepatotoxicity, nephrotoxicity, bone marrow suppression, and interstitial pneumonitis. MTX can cause birth defects. Men and women must use contraception while taking the drug.

Oral retinoids Retinoids may be especially useful against CLE with hyperkeratosis.

The retinoid etretinate was first used in1985 to treat CLE. Retinoids are considered a second-line therapy in CLE. They may be especially useful against CLE with hyperkeratosis. A randomized, multi-center, double-blind study reported that in patients with CLE, the effectiveness of 50 mg acitretin/daily was comparable to that of the HCQ 400 mg/daily, which is the gold standard (46 % compared to 50 %) [18]. Overall, the results of case reports on isotretinoin and acitretin show an effectiveness of 60–80 % [18]. Alitretinoin also appears to bring about improvement in SCLE, DLE, and SLE. There have also been reports on the successful use of retinoids in lupus nephritis. Acitretin and isotretinoin may be given at a dosage of 0.2 to 1.0 mg/kg body weight daily. Women of childbearing age must use adequate

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contraception, due to the risk of birth defects (up to 1 month after stopping for isotretinoin, and up to 2 years for acitretin).

Mycophenolate mofetil (MMF)/mycophenolate sodium (MPS) MMF has been shown to be effective, especially in the treatment of lupus nephritis.

MMF specifically and non-competitively inhibits inosine monophosphate dehydrogenase. The effect is reversible. This enzyme has a major influence on the proliferation of B and T lymphocytes and prevents apoptosis of activated lymphocytes [14, 16]. MMF has been shown to be effective, especially in the treatment of lupus nephritis. In CLE as well, small case series have shown that treatment with MMF achieved a significant reduction, or even complete clearance, of skin changes. The dosage of MMF is 1 to 3 g/daily, (MPS 720–2 160mg/daily). The side effects include increased susceptibility to infections and gastrointestinal side effects; MPS is generally better tolerated, and is comparably effective [24]. Adequate contraception should be ensured while taking MMF and for six weeks after stopping therapy.

Dapsone Dapsone is especially important in the treatment of bullous forms of the disease, when there is a high level of inflammatory activity, in mucocutaneous involvement, and in urticarial vasculitis.

Dapsone acts by inhibiting dihydrofolate reductase; it has antibiotic and anti-­ inflammatory properties. Dapsone is especially important in the treatment of ­bullous forms of the disease, when there is a high level of inflammatory activity, in mucocutaneous involvement, and in urticarial vasculitis. Yet, only about one-third of patients respond to treatment. Dapsone induces the development of methemoglobin and hemolytic anemia, which vary depending on dosage. Before starting treatment, glucose-6-phosphate dehydrogenase activity and Met-Hb levels should be measured. If fever, exanthem, hepatitis, or lymph node swelling occur, the possibility of dapsone-induced hypersensitivity syndrome (rare) should be considered. If confirmed, the drug should be stopped immediately.

Thalidomide and lenalidomide Thalidomide reduces the synthesis of tumor necrosis factor-α (TNF-α) and UV-induced apoptosis, thus decreasing inflammatory activity. One study reported an excellent response rate (98 %) after a two-week regimen of thalidomide. All patients in the study experienced clinical improvement, even taking lenalidomide, which generally has a milder side effect profile compared to thalidomide. Yet, given the risk of birth defects associated with both medications, as well as the high risk of peripheral neuropathy, both drugs (especially thalidomide) should be used only in exceptional instances. Controlled studies on the effectiveness of lenalidomide are still lacking, and there is a risk of disease exacerbation. It is therefore not the drug of choice. Women of childbearing age must use effective contraception and should be closely monitored for neurological side effects. The usual dosage is 50–100 mg/daily. When prescribing thalidomide, thorough patient education and documentation are essential.

Intravenous immunoglobulins (IVIG) As in SLE, polyvalent human IVIG has been successfully used to treat CLE [25]. Routine use is primarily limited by the high cost and the lack of reliable data on its effectiveness. IVIG should thus only be used in treatment refractory disease or if other treatment options are contraindicated. IVIG is given at a dosage of 1 to 2 g/kg of body weight every 4 weeks and then tapered to 0.5 g/kg of body weight [25].

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CME Article  Lupus erythematosus Clofazimine Clofazimine is an antibiotic with anti-inflammatory and immunosuppressant properties. It is used in the treatment of leprosy as well as granulomatous skin disorders such as Melkersson-Rosenthal syndrome, although it is not approved for use in Germany. According to the results of one study comparing the effectiveness of 100 mg clofazimine and 250 mg chloroquine, clofazimine was found to be similarly effective against cutaneous manifestations of SLE.

Azathioprine Azathioprine is a precursor of 6-mercaptopurine; it is an anti-metabolite of purine with cytotoxic and immunosuppressant properties [14, 16]. Azathioprine has been shown to lead to clinical improvement in CLE. Side effects include hepatotoxicity and bone marrow toxicity with susceptibility to infection as well as gastrointestinal complaints; the drug is known to interact with allopurinol among others. Given that the potentially reduced activity of thiopurine methyltransferase (TPMT) may lead to an overdose, the dosage should be titrated based on the patient's blood count and transaminase levels. The customary dosage is 1–2.5 mg/daily; the daily dosage is generally about 100 to 150 mg; the drug should be tapered over the course of therapy.

Cyclophosphamide Cyclophosphamide is an alkylating agent and cytostatic drug that is primarily used in SLE. It is less often administered to patients with CLE, given its significant side effects, including ovarian insufficiency, bladder cancer, and hematological neoplasia [16]. Cyclophosphamide and MMF have comparable clinical response rates in patients with lupus nephritis (81.8 % and 81.3 %).

Cyclosporine A Cyclosporine A (CyA) inhibits the activity of the phosphatase calcineurin and thus inhibits T-cell and B-cell activation. CyA is rarely used against CLE, due to its rather moderate effectiveness and the side effects related to the underlying LE, such as impaired renal function [16]. CyA may occasionally be used in systemic lupus, as it helps to limit the use of steroids. The dosage is 3–5 mg/kg of body weight per day, given in two single doses and subsequently tapered. The side effects of CyA, including arterial hypertension and renal toxicity, limit its long-term use (> 2 years).

Belimumab Belimumab (Benlysta®) is a purely human monoclonal antibody that targets BlyS. In July 2011, it was approved for the treatment of SLE by the European Drug Commission.

In the hope of developing a targeted treatment with a favorable side effect profile, in recent years various anti-B-cell antibodies have been tested clinically and pre-clinically [26]. Belimumab (Benlysta®) is a purely human monoclonal antibody that targets BlyS. In July 2011, it was approved for the treatment of SLE by the European Drug Commission. BlyS (B-lymphocyte stimulator; also known as B-cell activating factor/BAFF) belongs to the TNF-superfamily. It leads to proliferation and differentiation of B lymphocytes to immunoglobulin-producing plasma cells via activation of the NF-κB signal transduction pathway. Belimumab is well ­tolerated by patients with SLE. It reduces the frequency of flare-ups, decreases autoantibody production, and helps limit the use of steroids. The dosing schedule

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for intravenous belimumab is as follows: 10 mg/kg of body weight on days 0, 14, and 28 and then every 4 weeks. The most common side effects include infections (primarily of the upper respiratory tract), headaches, and blood changes.

Rituximab Rituximab is a chimeric anti-CD20 monoclonal antibody that depletes B cells via various mechanisms. Plasma cells remain untouched. The use of rituximab in SLE patients has produced contradictory results. Two current, randomized, placebo-controlled phase III studies found no advantage for SLE patients who took combination therapy with rituximab versus those who were given placebo with conventional immunosuppressant therapy. Rituximab has rarely been used in CLE patients.

Epratuzumab Epratuzumab is a humanized monoclonal antibody that targets CD22 on B cells. It influences the function and migration of B cells by inhibiting the B-cell receptor (BCR) signaling pathway [26]. A phase II study on epratuzumab reported that, at a cumulative dosage of 2,400 mg for 4 weeks, the drug considerably diminished disease activity in SLE patients compared to placebo. The results of two phase III studies on SLE patients have shown epratuzumab to have long-lasting efficacy and a good safety profile; it also helps limit steroid use [26].

Influence on signal transduction: kinase and phosphatase inhibitors Current developments are moving toward producing substances that have an acceptable side effect profile and which interfere in signal transduction pathways with pathogenetic relevance, or that interact with immune cells ­related to disease pathogenesis.

Current developments are moving toward producing substances that have an acceptable side effect profile and which interfere in signal transduction pathways with pathogenetic relevance, or that interact with immune cells related to disease pathogenesis [27]. Only a few of these small molecules have found their way into phase II studies on the treatment of SLE. Fostamatinib is a non-selective inhibitor of the kinase Syk and has been shown to be effective in clinical studies on rheumatoid arthritis, while JAK inhibitors, such as ruxolitinib, have already been approved for the treatment of myelofibrosis. Animal studies have shown both to be effective against SLE. This also applies to fasudil, a Rho-kinase inhibitor that has been in use for years in Japan to treat patients with cerebral vasospasms. mTOR inhibitors, such as rapamycin, have produced positive results in an open-label study on 9 patients with SLE. A phase II study on SLE patients has shown a quinolone-3-carboxamid (paquinimod, laquinimod) to have a positive benefit. Proteasome inhibitors, such as bortezomib, have yielded positive results in a case study with 13 SLE patients. Larger studies are needed in order to evaluate the therapeutic benefit of novel targeted SLE therapies that use small molecules. Still, the results that have been published until now seem promising. References 1 2 3 4

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Gilliam JN, Sontheimer RD. Distinctive cutaneous subsets in the spectrum of lupus erythematosus. J Am Acad Dermatol 1981; 4(4): 471–5. Albrecht J, Berlin JA, Braverman IM et al. Dermatology position paper on the revision of the 1982 ACR criteria for systemic lupus erythematosus. Lupus 2004; 13(11): 839–49. Tsuchida T. Classification of lupus erythematosus based upon Japanese patients. Autoimmun Rev 2009; 8(6): 453–5. Kanda N, Tsuchida T, Watanabe T, Tamaki K. Clinical features of systemic lupus erythematosus in men. Characteristics of the cutaneous manifestations. Dermatology 1996; 193(1): 6–10.

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Correspondence to

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Prof. Dr. med. Manfred Kunz Klinik für Dermatologie, ­Venerologie und Allergologie Universität Leipzig AöR

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Philipp-Rosenthal-Straße 23 04103 Leipzig

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E-mail: [email protected] uniklinik-leipzig.de

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Parodi A, Rebora A. ARA and EADV criteria for classification of systemic lupus ­ rythematosus in patients with cutaneous lupus erythematosus. Dermatology. 1997; e 194(3): 217–20. Petri M, Orbai AM, Alarcon GS et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012; 64(8): 2677–86. Ziemer M, Kardaun SH, Liss Y, Mockenhaupt M. Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with lupus erythematosus: a descriptive study of 17 cases from a national registry and review of the literature. Br J Dermatol 2012; 166(3): 575–600. Ackerman AB, Böer A, Bennin B, Gottlieb JG. Histologic Diagnosis of Inflammatory Skin Diseases. An Algorithmic Method Based on Pattern Analysis, 3 ed., New York: ­ArdorScribendi; 2005. Baltaci M, Fritsch P. Histologic features of cutaneous lupus erythematosus. ­Autoimmun Rev 2009; 8(6): 467–73. Biazar C, Sigges J, Patsinakidis N et al. Cutaneous lupus erythematosus: first ­multicenter database analysis of 1 002 patients from the European Society of ­Cutaneous Lupus Erythematosus (EUSCLE). Autoimmun Rev 2013; 12(3): 444–54. Ruland V, Haust M, Stilling RM et al. Updated analysis of standardized photoprovocation in patients with cutaneous lupus erythematosus. Arthritis Care Res (Hoboken) 2013; 65(5): 767–76. Ochsendorf FR. Use of antimalarials in dermatology. J Dtsch Dermatol Ges 2010; 8(10): 829–44. Marzano A, Vezzoli P, Crosti C. Drug-induced lupus: an update on its dermatologic aspects. Lupus 2009; 18(11): 935–40. Kuhn A, Ruland V, Bonsmann G. Cutaneous lupus erythematosus: update of ­t herapeutic options part I. J Am Acad Dermatol 2011; 65(6): e179–93. Jemec GB, Ullman S, Goodfield M et al. A randomized controlled trial of R-salbutamol for topical treatment of discoid lupus erythematosus. Br J Dermatol 2009; 161(6): 1365–70. Kuhn A, Ruland V, Bonsmann G. Cutaneous lupus erythematosus: update of ­t herapeutic options part II. J Am Acad Dermatol 2011; 65(6): e195–213. Luijten RK, Fritsch-Stork RD, Bijlsma JW, Derksen RH. The use of glucocorticoids in S ­ ystemic Lupus Erythematosus. After 60 years still more an art than science. ­Autoimmun Rev 2013; 12(5): 617–28. Ruzicka T, Sommerburg C, Goerz G et al. Treatment of cutaneous lupus erythematosus with acitretin and hydroxychloroquine. Br J Dermatol 1992; 127(5): 513–18. Lee SJ, Silverman E, Bargman JM. The role of antimalarial agents in the treatment of SLE and lupus nephritis. Nat Rev Nephrol 2011; 7(12): 718–29. Islam MN, Hossain M, Haq SA et al. Efficacy and safety of methotrexate in articular and cutaneous manifestations of systemic lupus erythematosus. Int J Rheum Dis 2012; 15(1): 62–8. Kuhn A, Specker C, Ruzicka T, Lehmann P. Methotrexate treatment for refractory ­subacute cutaneous lupus erythematosus. J Am Acad Dermatol 2002; 46(4): 600–3. Wenzel J, Brahler S, Bauer R et al. Efficacy and safety of methotrexate in recalcitrant cutaneous lupus erythematosus: results of a retrospective study in 43 patients. Br J Dermatol 2005; 153(1): 157–62. Miyawaki S, Nishiyama S, Aita T, Yoshinaga Y. The effect of methotrexate on ­improving serological abnormalities of patients with systemic lupus erythematosus. Mod ­Rheumatol 2013; 23(4): 659–66. Kreuter A, Tomi NS, Weiner SM et al. Mycophenolate sodium for subacute cutaneous lupus erythematosus resistant to standard therapy. Br J Dermatol 2007; 156(6): 1321–7. Bayry J, Negi VS, Kaveri SV. Intravenous immunoglobulin therapy in rheumatic ­diseases. Nat Rev Rheumatol 2011; 7(6): 349–59. Chan VS, Tsang HH, Tam RC et al. B-cell-targeted therapies in systemic lupus ­erythematosus. Cell Mol Immunol 2013; 10(2): 133–42. Markopoulou A, Kyttaris VC. Small molecules in the treatment of systemic lupus ­erythematosus. Clin Immunol 2013; 148(3): 359–68.

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Fragen zur Zertifizierung durch die DDA 1.

Welche der folgenden kutanen

LE-Manifestationen ist am wenigsten häufig mit einem SLE assoziiert? a) disseminierter diskoider LE b) lokalisierter diskoider LE c) papulosquamöser subakut kutaner LE d) anulärer subakut kutaner LE e) Lupus profundus

2. Welche Hautveränderung g ­ ehört nicht zu den LE-unspezifischen ­kutanen Manifestationen? a) periunguale Teleangiektasien b) Livedo racemosa c) Raynaud-Syndrom d) subkorneale Pustulose e) Thrombophlebitis

c) Melanophagen in der Epidermis d) Akanthose der Epidermis e) Atrophie der Basalmembran

6. Welcher Aussage ist richtig ­ insichtlich der LE-Diagnostik? h a) Die Durchführung des ­Lupusbandtests ist unverzichtbar für die Diagnose kutaner LE. b) Als erhöht gelten ANA ab einem ­T iter von 1 : 320. c) Erhöhte ANA-Titer sind oft mit einem erhöhten cANCA-Titer assoziiert. d) Positive anti-Ro/SSA-Werte werden am häufigsten beim chronisch ­diskoiden LE (CDLE) gefunden. e) Anti-ds-DNS-Antikörper sind beweisend für das Vorliegen eines SCLE.

d) Sie bewirken bei Patienten in ca. 30 % der Fälle eine irreversible ­Retinopathie. e) Mepacrin sollte Chloroquin und ­Hydroxychloroquin in der Therapie der kutanen LE vorgezogen werden.

9. Welche der folgenden Substanzen wird nicht zur Behandlung eines s­ ystemischen LE eingesetzt? a) Methotrexat (MTX) b) Mycophenolatmofetil (MMF) c) orale Retinoide d) Cetuximab e) Belimumab

10. Welche Aussage zu klassischen 3. Welches ist die häufigste klinische

7. Welche Aussage bzgl. der

Manifestationsform des kutanen LE? a) Lupus tumidus b) akut kutaner LE c) diskoider LE d) Lupus-Pannikulitis e) Chilblain Lupus

­Prävention und Therapie eines

4. Welche der folgenden ­Hautveränderungen gehört nicht zu den epidermodermalen Varianten des LE? a) diskoider LE b) subakut kutaner LE c) Rowell-Syndrom d) toxisch epidermale Nekrolyse (TEN)-artiger LE e) Lupus-Pannikulitis

­ utanen LE trifft zu? k a) Bei etwa 25 % der kutanen LE-­ Patienten ist die Erkrankung ­medikamentös induziert. b) Prävention spielt bei der Vermeidung eines kutanen LE keine Rolle. c) Gegenwärtig sind für die systemische Therapie des kutanen LE keine Medikamente zugelassen. d) Topische Glukokortikosteroide ­spielen in der Therapie eine ­untergeordnete Rolle. e) Salbutamol wurde kürzlich für die Therapie des kutanen LE zugelassen.

8. Welche Aussage zu ­Antimalariamitteln wie Chloroquin

5. Welche Aussage zur Histopathologie des kutanen LE ist richtig? a) oberflächliches und tiefer gehendes, dichtes, perivaskuläres Infiltrat aus neutrophilen Granulozyten b) fokale vakuoläre Degeneration ­entlang der dermoepidermalen Junktionszone

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und Hydroxychloroquin trifft zu? a) Sie induzieren die Expression von Toll-like-Rezeptoren auf ­Entzündungszellen. b) Sie haben eine Wirksamkeit bei 50 bis über 80 % der Patienten. c) Die Dosierungsempfehlungen für Chloroquin und Hydroxychloroquin sind identisch.

© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1204

­Nebenwirkungen von beim LE ­eingesetzten Behandlungsverfahren trifft nicht zu? a) Topische Glukokortikosteroide – Hautatrophie, Teleangiektasien b) Lasertherapie - Köbnerisierung c) Systemische Glukokortikosteroide – Cushing Syndrom, Hyperglykämie, Osteoporose d) Dapson – Arterielle Hypertonie e) Chloroquin - Retinopathie

Liebe Leserinnen und Leser, der Einsendeschluss an die DDA für diese Ausgabe ist der 19. Mai 2014. Die richtige Lösung zum Thema „Lokale Palliativversorgung von Hautmetastasen in der Dermatoonkologie“ in Heft 11 (November 2013) ist: 1b, 2d, 3c, 4e, 5b, 6b, 7c, 8b, 9d, 10d. Bitte verwenden Sie für Ihre Einsendung das aktuelle Formblatt auf der folgenden Seite oder aber geben Sie Ihre Lösung online unter http://jddg.akademie-dda. de ein.

Lupus erythematosus. Part II: clinical picture, diagnosis and treatment.

Lupus erythematosus (LE) is an important dermatologic autoimmune disease. In many respects, it may be regarded as a model autoimmune disease due to it...
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