LUPUS LINEEGUIDA S2K DIAGNOSI .pdf

 Guideline DOI: 10.1111/ddg.14492 S2k guideline: Diagn...

 Guideline DOI: 10.1111/ddg.14492 S2k guideline: Diagnosis and management of cutaneous lupus erythematosus – Part 1: Classification, diagnosis, prevention, activity scores AWMF registry no.: 013–060 Margitta Worm1, Miriam Zidane2, Lisa Eisert3, Rebecca Validity of this guideline: The guideline Fischer-Betz4, Ivan Foeldvari5, Claudia Günther6, Christof is valid until 24.03.2023. Iking-Konert 7, Alexander Kreuter8, Ulf Müller-Ladner9, Alexander Professional Societies involved: Nast2, Falk Ochsendorf 10, Matthias Schneider4, Michael Sticherling11, Klaus Tenbrock12, Jörg Wenzel13, Annegret Kuhn14 – German Dermatological Society (Deutsche Dermatologische Gesell- (1) Department of Dermatology, Venereology and Allergology, Division of Allergology schaf, DDG) and Immunology Charité – Universitätsmedizin Berlin, corporate member of Free – German Society for Rheumatology University of Berlin, Humboldt University of Berlin, and Berlin Institute of Health (Deutsche Gesellschaft für Rheu- (2) Department of Dermatology, Venereology and Allergology, Division of Evidence- matologie e.V. DGRh) Based Medicine Charité – Universitätsmedizin Berlin, corporate member of Free – German Society for Pediatric Rheu- University of Berlin, Humboldt University of Berlin, and Berlin Institute of Health matology (Gesellschaft für Kinder- (3) Department of Dermatology and Venereology, Vivantes Klinikum Neukölln, und Jugendrheumatologie e.V., Berlin GKJR) (4) Clinic and Functional Division for Rheumatology, University Hospital Düsseldorf, Düsseldorf (5) Hamburg Center for Pediatric and Adolescent Rheumatology, Hamburg (6) Department of Dermatology, University Hospital Carl Gustav Carus Dresden, and Technical University of Dresden, Dresden (7) III. Medical Clinic and Polyclinic, Section Rheumatology, University Hospital Hambug-Eppendorf, Hamburg (8) Dermatology, Venereology and Allergology, Helios St. Elisabeth Hospital Oberhausen, and University of Witten-Herdecke, Oberhausen (9) Department of Rheumatology and Clinical Immunology, Kerckhoff Hospital GmbH, Bad Nauheim (10) Department of Dermatology, Venereology and Allergology, University Hospital Frankfurt, Frankfurt am Main (11) Dermatological Department, University Hospital Erlangen, Erlangen (12) Department of Pediatrics and Adolescent Medicine, University Hospital RWTH Aachen, Aachen (13) Dermatological Department, University Hospital Bonn, Bonn (14) Medical Director, Hospital Passau, Passau, University of Münster, Münster, Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Center, Amsterdam, Niederlande © 2021 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft. | JDDG | 1610-0379/2021/1908 1236 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.  16100387, 2021, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ddg.14492 by CochraneItalia, Wiley Online Library on [24/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Guideline S2k guideline: Cutaneous lupus erythematosus – Part 1 Introduction Table 2 Duesseldorf Classification of lupus erythematosus, modified in accordance to [1, 6, 7]. Table 1 shows the terms and symbols used for the standardi- zed representation of our recommendations. Acute cutaneous lupus erythematosus (ACLE) Subacute cutaneous lupus erythematosus (SCLE) Clinical introduction Chronic cutaneous lupus erythematosus (CCLE) – Discoid lupus erythematosus (DLE) Cutaneous lupus erythematosus (CLE) is a rare, inflammatory – Chilblain lupus erythematosus (CHLE) autoimmune skin disease with heterogeneous clinical appearan- – Lupus erythematosus profundus/panniculitis (LEP) ce. Currently, there is no treatment specifically approved for this Intermittent cutaneous lupus erythematosus (ICLE) disease. Topical and systemic medications are used off label. The – Lupus erythematosus tumidus (LET) goal of this guideline is to provide consensus-based recommen- dations on the diagnostics and treatment of patients with CLE, siehe Kommentar in accordance with the existing German S1 further differentiated based on clinical, histopathological, guideline from 2009 and with the European S2K guideline serological, and genetic findings. This was modified and pre-. Diagnostik und Therapie des kutanen Lupus erythemato- sented in the “Düsseldorf Classification” in 2004 (Table 2) des, AWMF-Register-Nr.: 013-060, 2020, www.awmf.org [6, 7]. Examples of non-LE-specific cutaneous lesions that may quite frequently be associated with SLE include vascular Classification, pathophysiology, and skin disorders (periungual teleangiactasia, livedo racemosa, thrombophlebitis, Raynaud phenomenon). epidemiology Tables 3 and 4 summarize the clinical appearance and special characteristics of the various forms of chronic CLE Classification (CCLE) and the intermittend CLE (ICLE). The clinical signs Lupus erythematosus (LE) is a heterogeneous, inflammatory autoimmune disease which can involve many organs with a Table 3 Chronic cutaneous lupus erythematosus (CCLE), variable course. Systemic lupus erythematosus (SLE) must according to. be differentiated from cutaneous lupus erythematosus (CLE). Discoid lupus erythematosus (DLE) This guideline only covers the disease of CLE, even though in the literature CLE may not always be differentiated Clinical appearance from cutaneous lesions associated with SLE. The classifi-  Localized type (ca. 80 %) cation of the various skin manifestations of CLE is originally – Face and capillitium based on the work of James N. Gilliam who differentiated  Disseminated type (about 20 %, frequently associated between LE-specific and non-LE-specific cutaneous lesions with SLE) according to histological criteria. LE-specific cutaneous – Also upper trunk and extensor sides of limbs manifestations (cutaneous lupus erythematosus, CLE) are  DLE of the oral mucous membranes – Buccal mucous membranes >> palate Special characteristics Table 1 Strengths of recommendation – wording, symbo- lism and interpretation (modified in accordance to Kamins-  Most common type of CCLE ki-Hartenthaler et al., 2014).  Discoid erythematous plaques with tightly adhering follicular hyperkeratoses and hyperesthesia Strength of Wording Symbol  Manual removal of keratosis (“carpet tack sign”) is pain- recommendation ful Strong recommendation recommended ↑↑  Active margin with erythema and hyperpigmentation in favor of an approach  Scarring with central atrophy and hypopigmentation, scarred alopecia in hirsute areas Weak recommendation in suggested ↑  Discoid lesions in the lip area > buccal mucous favor of an approach membranes No recommendation as to may be considered 0  Mutilations in the area of nose and mouth, vermicular approach perioral scarring Recommendation against not recommended ↓  Provocation by irritant stimuli (Koebner’s phenome- an approach non) may occur Continued © 2021 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft. | JDDG | 1610-0379/2021/1908 1237  16100387, 2021, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ddg.14492 by CochraneItalia, Wiley Online Library on [24/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Guideline S2k guideline: Cutaneous lupus erythematosus – Part 1  In rare cases, squamous cell carcinoma may develop in Table 4 Intermittent cutaneous lupus erythematosus (ICLE), healed scars according to.  ANA with high titers (rarely, in ca. 5 %), usually no anti- Lupus erythematosus tumidus (LET) ds-DNA antibodies, rarely antibodies against Ro/SSA or Clinical appearance U1-RNP  Succulent, indurated, urticaria-like erythematous pla-  In 10 % of cases, DLE is the first sign of SLE ques with smooth surface without involvement of the Lupus erythematosus profundus (LEP; Synonym: LE epidermis panniculitis)  Lesions are often arranged in annular or sometimes Clinical appearance and special characteristics semicircular patterns  Subcutaneous, nodular or discoid, firm infiltrations,  Predilection sites: areas exposed to light (especially with secondary adherence to the overlaying skin face, upper trunk, cleavage, extensor sides of the arms)  Surface of the lesions: inflammatory erythema, no alte-  Healing without scars or pigment disorders ration, or simultaneous DLE Special characteristics  Predilection sites: Gluteal or hip area, thighs, upper  Pronounced photosensitivity (in > 70 % positive photo- arms, face, chest provocation test with UVA and/or UVB)  In rare cases, periorbital edema may occur as an initial  ANA in 10–30 % positive, anti-Ro/SSA and anti-La/SSB sign antibodies in about 5 %  Ulceration and calcification may occur  Varying course with very good prognosis, sponta-  Healing may result in scars and deep lipatrophy neous remission may occur  ANA positive in up to 75 %; usually no anti-ds-DNA antibodies, occurrence of anti-ds-DNA antibodies may an autoimmune response against the own epidermis occurs signify transition into SLE [10–12]. The histological correlation of this specific anti-epi-  ACR criteria from 1982 are formally fulfilled in 35–50 %, dermal inflammation is the so-called interface dermatitis. association with SLE is more rare This is characterized by infiltration of the basal epidermal Chilblain lupus erythematosus (CHLE) Clinical appearance layer with cytotoxic lymphocytes and plasmacytoid dendritic and special characteristics cells (pDC), but also cell death of local keratinocytes. Based  Livid swellings that are painful on pressure, as well as on the CLE subtype and the individual patient, different ef- large, cushion-like nodes, partly with central erosion fector mechanisms of the immune system are involved. These and ulceration include the adaptive immune response (mainly auto antibo-  Predilection sites: symmetrical acral areas exposed to dies, T cells) as well as the innate immune response with ac- the cold (dorsal and marginal regions of the fingers, tivation of cell death, cytokine, and DAMP (damage-associ- tips of the toes, heels, ears, nose) ated molecular pattern) pathways. Central pro-inflammatory  EIGENER PUNKT: Occurrence in the cold and damp factors include type I/III interferons and associated cytokines seasons or after a drop in temperature (mainly CXCL10) which are expressed both by pDC and ke-  Clinical and histological differentiation from genuine ratinocytes, and are required for the recruitment of CXCR3+ chilblains (perniones) is difficult effector cells. A key to understanding the development of  ANA, anti-Ro/SSA antibodies and positive rheumatoid skin lesions in CLE is that factors from the adaptive immune factors are variable; usually no anti-ds-DNA antibodies system (which is actually downstream) can trigger pathways  Associated with SLE in about 20 % of the (primary) innate immune system, resulting in a “per-  Familial “Chilblain lupus”: First description of a mono- manently activated short circuit”. genic, inherited form of CLE Epidemiology and special characteristics of acute CLE (ACLE) and subacu- te CLE (SCLE) can be found in the supplement. Due to the various subtypes, there is only a limited amount of valid data on the prevalence of CLE. Transition from CLE Pathophysiology to SLE has been reported for 20 % of CLE patients within three to five years [15–18]. Up to 30 % of all CLE patients CLE is a cutaneous autoimmune disease with simultaneous develop more than one subtype [17, 18]. CLE usually appears activation of the innate and adaptive immune system [8, 9]. during the third to fourth decade of life, and the females to Depending on the patient’s individual genetic disposition, and males gender ratio is much lower than with SLE (3 : 1 to 3 : 2) to some extent via immunostimulatory triggers (i.a. UV rays), (9 : 1) [19, 20]. © 2021 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft. | JDDG | 1610-0379/2021/1908 1238  16100387, 2021, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ddg.14492 by CochraneItalia, Wiley Online Library on [24/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Guideline S2k guideline: Cutaneous lupus erythematosus – Part 1 In three quarters of all patients with SLE, skin lesions Special stains develop during the course of the disease, and in one quarter the skin is even the initial manifestation. A Swedish publica- Special stains may help to confirm the diagnosis of CLE but tion puts the incidence of CLE at 4.0 per 100,000. Wit- are not obligatory. Some examples are alcian blue stains (der- hin the subtype of CCLE, discoid lupus erythematosus (DLE) mal mucin deposits), PAS stains (basal laminae) , and is the most common form at 80 %. DLE is most common detection of plasmacytoid dendritic cells (BDCA2, CD123) in African Americans, while SCLE occurs predominantly in. Surrogate markers of IFN activation (MxA) can visuali- light-skinned European ethnicities. Chilblain LE (CHLE) ze activation of the innate immune system within the lesion, and LE tumidus (LET) are found mostly in Europe [22–25]. which is characteristic for CLE. Diagnostics Direct immunofluorescence Diagnostics Direct immunofluorescence (DIF) can show lesional granular deposits of C3 as well as IgG and IgM in CLE. In uncertain Diagnostics of CLE should be based on the clinical and his- cases, this test can help confirm the diagnosis of LE [26, 27, tological findings. Patients with CLE without systemic invol- 30]. It should be noted that false-positive results may occur vement often lack detectable autoantibodies, but if present in skin areas exposed to light, especially in rosacea. the autoanti-bodies may help to support the diagnosis and to Non-lesional skin not exposed to light may show a higher better assess the prognosis. number of positive DIF in SLE patients (lupus band) [30, 32]. However, the authors would like to stress that this test is in- Histology sufficient to confirm the diagnosis of SLE, which must always be correlated with the clinical findings. If CLE is suspected, the diagnosis should always be confirmed via skin biopsy (except in cases of ACLE if SLE has already Recommendation Strength Agreement been confirmed). Ideally, the specimen should be obtained A lesional biopsy is recommen- ↑↑ 100 % from an active, non-treated lesion. Active lesions typically ded for histological confirma- show interface dermatitis with anti-epidermal lymphocytic tion of a clinical of CLE diagno- infiltration, vacuolization of basal keratinocytes, and colloid sis. Exceptions can be made in bodies [26, 27]. Acanthosis, dermal infiltrations, and mucin cases of ‘butterfly rash’ and/or deposits may vary depending on the CLE subtype (Table 5). mucosal lesions. Special stains as well as ↑ 100 % Table 5 Prominent histological and immunohistological cha- immunohistology are sug- racteristics of lesions from cutaneous lupus erythematosus gested to confirm diagnosis (CLE), modified in accordance to. (examples include PAS, alcian blue, CD123, MxA). Subtypes Histology/Immunohistology Direct immunofluoresence ↑ 100 % CLE  Interface dermatitis (DIF) is suggested in cases  Hydropic degeneration of the basal where differential diagnosis is epidermis difficult.  Lymphoid infiltration (mostly plas- Analysis of lesions not exposed ↑↑ macytoid dendritic cells and T cells) to light is recommended.  Dermal mucin deposits  Strong expression of chemokines Direct immunofluoresence ↓ 100 % regulated by interferons (MxA, CXCL10) (DIF) of non-lesional skin exposed to light is not ACLE  Discrete infiltrations with moderate recommended. interface dermatitis  Sporadic neutrophils in the infiltrations as well as nuclear detritus Photoprovocation SCLE  Interface dermatitis with few cells and Photoprovocation with UV light according to a standard cutaneous, perivascular infiltrations protocol is appropriate for confirming the diagnosis of pho-  Moderate mucin deposits tosensitive CLE subtypes. After UV exposure, specific © 2021 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft. | JDDG | 1610-0379/2021/1908 1239  16100387, 2021, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ddg.14492 by CochraneItalia, Wiley Online Library on [24/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Guideline S2k guideline: Cutaneous lupus erythematosus – Part 1 CLE lesions will only appear after a latency of 8 ± 4.6 days Table 6 Continued. ANSER and will then persist for a considerable time. In contrast, Arthritis Synovitis in ≥ 2 joints 6 other photodermatoses such as polymorphous light eruption or pain on pressure in (PLE) will appear much earlier after UV exposure and the ≥ 2 joints with morning lesions will subsequently resolve. In addition to the clinical stiffness ≥ 30 minutes evaluation, UV-induced CLE lesions can be confirmed via Neurology Delirium 2 biopsy. Psychosis 3 Recommendation Strength Agreement Seizures 5 In special cases, standardized ↑ 100 % Serositis Pleural or pericardial 5 photoprovocation performed effusion by experienced investigators is suggested (for example to Acute pericarditis 6 exclude CLE, or to differentia- Hematology Leukopenia 3 te between CLE and polymor- Thrombocytopenia 4 phous light eruption). Autoimmune hemolysis 4 Classification criteria of SLE Kidneys Proteinuria > 0.5 g/24 h 4 Lupus nephritis (histol.) 8 A working group from the European League Against Rheu- Type II, V matism (EULAR) and the American College of Rheumatolo- Lupus nephritis (histol.) 10 gy (ACR) has developed a scoring system for classification of Type III, IV SLE [34, 35] (Table 6). This has replaced the former ACR cri- Immunologi- Weighting cal criteria FCSD Table 6 New EULAR/ACR SLE classification criteria, accor- Antiphospho- aCL>40 GPL or aß2G- 2 ding to. lipid AB PI>40 GPL or LA + Prerequisite ANA (HEp2-IFT) ≥ 1 : 80 (may vary de- Complement Low C3 or C4 3 pending on the normal range of the local Low C3 and C4 4 laboratory) Highly Anti-ds-DNA AB 6 Basic – If other causes are present, such as in- specific auto- Anti-Sm AB conditions fection, neoplasia, medications, or other antibodies diseases, a criterion is not counted. Classification SLE classification: ≥ 10 points – At least one criterion needs to be cur- EULAR/ACR criteria: sensitivity 98 %, specificity 97 % rently present. – Criteria are fulfilled if they have been present (documented) at any time. – Criteria do not have to be present si- teria (established in 1982, revised in 1997) and the SCLICC multaneously. criteria (Systemic Lupus Erythematosus Collaborating Cli- – Within each domain, only the highest nics Group, established in 2012). These two scores put score is counted for the total score. equal emphasis on serological and clinical criteria. So far, Clinical Weighting four out of eleven criteria ACR criteria from 1982 contained domains and mucocutaneous manifestations (butterfly rash, discoid lesi- criteria ons, light sensitivity, and oral ulcerations). Light sensitivity, in particular, can easily be interpreted differently, resulting Constitutional Fever 2 almost certainly in over-estimation of SLE prevalence. Skin Non-scarring alopecia 2 It has been shown that about 50 % of SLE patients, 10 % Oral ulcers 2 of DLE patients, and practically all ACLE patients will ful- SCLE or DLE 4 fill the criteria for SLE without necessarily having systemic (organ) involvement. The new criteria are designed for better ACLE 6 differentiation between CLE and SLE. SAC PIU’ ALOPECIA E ULCERE ORALI © 2021 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft. | JDDG | 1610-0379/2021/1908 1240  16100387, 2021, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ddg.14492 by CochraneItalia, Wiley Online Library on [24/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Guideline S2k guideline: Cutaneous lupus erythematosus – Part 1 Recommendation Strength Agreement de or confirm organ involvement. Laboratory investigations are, however, not only useful in initial diagnostics but also Diagnosis: ↑↑ 100 % for evaluation of prognosis and activity. In addition, drug The use of the 2019 EULAR/ side effects need to be monitored. We cannot give eviden- ACR criteria is recommended in ce-based recommendations for the frequency of laboratory order to differentiate CLE from investigations – this depends on individual factors such as (Table 6). severity and activity of the (cutaneous) disease, treatment, Monitoring: ↑ 100 % comorbidities and their treatment, as well as previous fin- For any CLE patient, a dings (such as detection of ANA or ENA) and changes in reassessment of the 2019 laboratory values (such as anti-ds-DNA antibodies or com- EULAR/ACR criteria is sugge- plement). Table 7 offers a list of recommended blood analyses sted either once a year and/or in patients with CLE, including their significance. in case of clinical/laboratory changes. Recommendation Strength Agreement In CLE patients, it is recom- ↑↑ 100 % Laboratory parameters mended to analyse the blood and urine parameters listed in In patients with ACLE (which is most frequently associated Table 6 for diagnosis as well as with SLE) and/or in patients with SCLE (frequently associa- monitoring of disease activity ted with arthritis or other moderate organ involvement), la- and toxic drug side effects. boratory investigations should always be performed to exclu- Table 7 Recommended blood tests for patients with CLE and their relevance. Test Remarks Blood count including Hematological disorders (anemia, leukopenia or lymphopenia as well as thrombocytopenia) are differential blood count part of the SLE criteria but have also been reported to occur in CLE patients (anemia: 2–27 %; leukopenia: 0–30 %; thrombocytopenia: 2–4 % of patients). Abnormal values (mostly low cell counts) may either be an expression of disease activity or a to- xic side effect of drug treatment. ESR and CRP ESR is typically increased in SLE patients (due to hypergammaglobulinemia, among other rea- sons) but may also be increased in 20–50 % of CLE patients. CRP increase in CLE/SLE usually indicates infection but may also be a sign of serositis or arthritis. If it can be explained by activity (for example arthritis) it is suitable for monitoring. Creatinine and eGFR Serum creatinine offers very low sensitivity in the early stages of lupus nephritis. Increases are frequently found only once renal function is severely impaired (blind area). Levels also depend on the patient’s age and (among other things) muscle mass. Estimated glo- merular filtration rates (eGFR) according to a standardized formula, or (rarely nowadays) creatini- ne clearance from a 24-hour urine collection are therefore more reliable. Elevated or increasing creatinine levels necessitate early consultation of a specialist for internal medicine/nephrology. Urinalysis, urine sedi- Urinalysis is required to screen for renal involvement. In case of abnormal values, urinalysis ment, and proteinuria should be repeated and the urine sediment investigated. The protein (or albumin) to creatinine ratio in morning urine can be used for screening or moni- toring of proteinuria. 24-hour urine collection for analysis is usually unnecessary. Reproducible abnormalities in urinalysis (for example erythrocyturia or proteinuria) necessitate consultation of a specialist for internal medicine/nephrology! Continued © 2021 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft. | JDDG | 1610-0379/2021/1908 1241  16100387, 2021, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ddg.14492 by CochraneItalia, Wiley Online Library on [24/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Guideline S2k guideline: Cutaneous lupus erythematosus – Part 1 Table 7 Continued. Test Remarks Hepatic function: ASAT, Involvement of the liver in the sense of an overlap syndrome with autoimmune hepatitis (AIH) is ALAT, γGT and ALP, bili- rare in patients with CLE/SLE. Increased hepatic enzymes thus usually result from toxic side ef- rubin if indicated fects induced by medications (drug-induced liver injury [DILI]). Hepatic function should be monitored before and during medical treatment. Early consulta- tion of internal medicine specialists and investigation of increased values (for example due to infection) is recommended. CK and LDH Increased CK may (rarely) result from myositis associated with SLE. In very rare cases, hydroxychloroquine treatment may cause myopathy with increase of CK. LDH may result from hemolysis; this can be investigated by determining haptoglobin. Electrophoresis Electropheoresis may detect alterations of serum proteins: Albumin is decreased in patients with lupus nephritis, 2–4 % of patients have monoclonal gammopathy (usually MGUS). Initial investiga- tion to exclude other disorders (monoclonal gammopathies, IgA deficiency, hyper-IgE syndrome). Antinuclear antibodies ANA determination is the classic screening test for connective tissue diseases and should be perfor- (ANA) (HEp-2 cell test) med in all patients with CLE. If present, ANA usually show low titers in CLE (≤ 1 : 320, note: this may vary between laboratories). Positive ANA is an obligatory criterion when diagnosing SLE (Table 6). Nowadays, ANA are described by their fluorescence according to the AC nomenclature. Positive ANA should be further specified via ENA. The frequency of ANA and ENA varies depen- ding on the clinical CLE subtype. Anti-Ro/SS-A antibodies (and less pronounced anti-La/SS-B), for example, are typical for SCLE. Anti-histone antibodies are frequently found in drug-induced LE while antibodies against ds-DNA and/or Sm are frequently detected in SLE (they are included in the new SLE criteria) but are not typical for CLE. Anti-ds-DNA antibodies can be used for monito- ring disease courses and activity. Antiphospholipid AB Antiphospholipid antibodies (APS-AB, most frequently cardiolipin, beta-2 glycoprotein, and the (APS-AB) and lupus lupus anticoagulant) are included in the EULAR and ACR/SLICC criteria for SLE. anticoagulant They are serological markers for the antiphospholipid antibody syndrome (APS). APS antibodies are found in various CLE subtypes with large variations in frequency (5.8–68 %). Detection of (significant) APS-AB levels indicates SLE rather than CLE. Complement C3 and C4 C3 and/ or C4 are included in the EULAR and ACR/SLICC criteria for SLE. Low levels of C3 and/or C4 are very typical for SLE while the levels are usually normal in CLE. If low levels are present, C3 and C4 are particularly well suited for monitoring disease course and activity. High levels of C3 or C4 can for example be found in infection (acute phase protein). In CLE patients, CH50, C1q, and anti-C1q antibodies should only be determined if there is a strong suspicion of transition into SLE. Organ-specific diagnostics and interdisciplinary In SLE patients, cardiovascular risk (hypertension, hy- investigations perlipidemia) is increased due to various risk factors, both disease-specific (lupus nephritis, permanent disease In case of abnormalities in the laboratory or urinalysis investi- activity, corticosteroids) and non-specific. Thus, appropriate gations, further diagnostic steps such as X-rays, MRI, echocar- screening should be performed. diography, or ultrasound must be initiated. The musculoskele- tal, hematological, renal, cardiopulmonary, and neurological Recommendation Strength Agreement systems need to be monitored. Studies have shown that 10– Based on clinical and/or labo- ↑↑ 100 % 15 % of CLE patients developed systemic organ involvement ratory findings, organ-specific within eight years. Case reports have also described CLE as a diagnostics or referral to an paraneoplastic disease; this applies almost exclusively to SCLE appropriate specialist is recom- [1, 37, 38]. Appropriate screening investigations should be re- mended. commended to the patient, and their primary care physician informed. © 2021 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft. | JDDG | 1610-0379/2021/1908 1242  16100387, 2021, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ddg.14492 by CochraneItalia, Wiley Online Library on [24/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Guideline S2k guideline: Cutaneous lupus erythematosus – Part 1 Recommendation Strength Agreement Prevention Monitoring of cardiovascular ↑↑ 90.1 % Sun protection risk factors is recommended as part of basic diagnostics. CLE patients who show induction or exacerbation on expo- Participation in the generally re- ↑↑ 100 % sure to UV radiation are very sensitive to light. Consistent sun commended cancer screening protection is therefore an important preventive strategy [41, examinations (skin, colon, 42]. Sun exposure should be avoided especially around noon gynecology, prostate) is recom- (11 am to 3 pm), and artificial UV radiation (such as tanning mended for CLE patients. beds) is not recommended. Patients should be warned that clear glass (including car windows) does not protect against Differential diagnoses UV-A radiation [43, 44]. Depending on the CLE subtype, various differential diagno- Apart from sun-protective clothing and broad-brim- ses need to be considered (summary in Table 8). Polymorphic med hats, sunscreen with chemical and/or mineral UV-A light eruption (solar rash) is an important differential dia- and UV-B filters is essential. This should be applied in suf- gnosis; however, this has also been found to be frequently ficient quantity (about 2 mg/cm²) 20–30 minutes before sun associated with SCLE or DLE before or after diagnosis. exposure [45, 46]. A double-blind, intra-individual compari- son study in eleven CLE patients who had developed speci- Table 8 Differential diagnosis for cutaneous lupus erythe- fic lesions on photoprovocation found that one of the three matosus, in accordance to. test preparations (with Mexoryl SX/XL, among other ingre- dients) was able to prevent induction of skin lesions in 100 % Subtype Differential diagnoses of cases. A retrospective analysis using the same sun- ACLE screen confirmed these results in 96 % of patients (47 CLE, – localized Dermatomyositis, rosacea, seborrheic 4 SLE). Another prospective, randomized, double-blind, eczema, tinea faciei (facial ringworm), intra-individual, vehicle-controlled study showed prevention erysipelas, perioral dermatitis of CLE during photoprovocation in 16 patients after applica- – generalized Viral or drug-induced exanthema, erythe- tion of a broad-band chemical and mineral UV-A/UV-B filter ma multiforme, toxic epidermal necrolysis with added vitamin E as an antioxidant. The sunscreens used in the abovementioned studies contained additional ti- SCLE Tinea corporis, psoriasis vulgaris, mycosis tanium dioxide as a mineral sunscreen. For CLE as well as fungoides, erythema multiforme/toxic other severe photodermatoses, sunscreens are not reimbur- epidermal necrolysis, erythema annulare sed by health insurance companies although this preventative centrifugum (EAC), erythema gyratum strategy may reduce the need for topical and systemic medi- repens, drug rash, nummular eczema, cations [49, 50]. seborrheic eczema DLE Tinea faciei, actinic keratosis, lupus Recommendation Strength Agreement vulgaris, sarcoidosis Apart from sun protective ↑↑ 100 % LEP Various forms of panniculitis, subcuta- clothing, consistent use of neous sarcoidosis, polyarteritis nodosa, sunscreen in exposed areas is malignant lymphoma (especially sub- recommended at all stages of cutaneous panniculitis-like T-cell lympho- the disease, irrespective of the ma), morphea profunda, subcutaneous extent and the topical or sys- granuloma annulare temic medication used. CHLE Perniones (chilblains), lupus pernio (chro- nic form of skin sarcoidosis on the acra), There are currently no approved medications for tre- acral vasculitis/vasculopathy ating CLE, either topical or systemic. Treatment is based LET Jessner lymphocytic infiltration (JLIS)/pal- on a small number of randomized controlled trials. The- pable migratory arciform erythema, poly- re are, however, consensus-based European recommen- morphic light eruption, pseudolymhoma, dations for the treatment of CLE patients which are B-cell lymphoma, plaque-like cutaneous reflected in an algorithm [2, 51]. This algorithm contains mucinosis, solar urticaria first-line, second-line, and third-line treatments. It has © 2021 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft. | JDDG | 1610-0379/2021/1908 1243  16100387, 2021, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ddg.14492 by CochraneItalia, Wiley Online Library on [24/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Guideline S2k guideline: Cutaneous lupus erythematosus – Part 1 been modified in the development of this guideline. Me- for evaluating quality of life in CLE patients. However, the pacrine is frequently not reimbursed by health insurance use of general dermatological quality of life scores can be and is thus only mentioned as a possible addition in the recommended, such as the DLQI (Dermatology Life Quali- first-line treatment. ty Index) or the Skindex-29. Treatment monitoring should always take into account that cosmetic aspects may strongly Use of activity scores influence quality of life, in particular as regards scarring lesi- ons on the face and scalp. CLASI/RCLASI Recommendation Strength Agreement Several methods have been developed to assess disease ac- Diagnosis and monitoring: ↑ 100 % tivity in SLE, including ECLAM (European Consensus Use of the DLQI or Skindex-29 lupus Activity Measurement), BILAG (British Isles lupus (skin-specific methods for Assessment Group), SLAM (Systemic lupus Activity Mea- evaluating quality of life) is sure), or SELENA-SLEDAI (Systemic lupus Erythematosus suggested for evaluating qua- Disease Activity Index). These scores encompass a broad lity of life in CLE patients. spectrum of potential organ involvement in SLE (including skin involvement) but are not suited for precisely assessing the spectrum of cutaneous symptoms in CLE or SLE. In Prognosis 2005, a validated clinical score for assessing activity and intensity of CLE was introduced (Cutaneous lupus Erythe- CLE subtypes may, with varying frequency, lead to syste- matosus Disease Area and Severity Index [CLASI]). The mic organ involvement and thus transition into SLE. CLASI can be used to evaluate disease severity: Mild disea- A study with 28 male and 11 female patients showed that se = CLASI activity 0–9, moderate disease: 10–20, severe disseminated skin lesions in DLE are significantly more disease: 21–70. CLASI reduction by four points or 20 % common in males than in females. While transition may be regarded as a therapeutic response. A revised form into SLE is seen in < 5 % of cases in DLE, the most com- of the CLASI (RCLASI) includes additional clinical criteria, mon subtype of CCLE, SCLE will lead to systemic organ such as edema/infiltration or subcutaneous nodes/plaques, involvement in about 10–15 % of cases, mostly with mild for the various forms of CLE. Validity and practicability of symptoms. If minimal symptoms are included, the propor- the RCLASI have been confirmed in a reliability analysis. tion of patients with extracutaneous involvement is 14– Apart from evaluating therapeutic response and monitoring 27 % in DLE and 60–70 % in SCLE. The most common treatment, this score is also useful in diagnosing the various symptoms are arthralgia/arthritis, and proteinuria. In CLE subtypes [16, 52–59]. SCLE, acral vasculitis is frequently associated with joint involvement. Patients with disseminated DLE show more frequent extracutaneous involvement and thus have Recommendation Strength Agreement a higher risk of transition into SLE than patients with Diagnosis: ↑ 100 % localized DLE on the face and scalp. A prospective Use of CLASI or RCLASI is sug- multicenter study confirmed these findings in 296 LE pati- gested for evaluating disease ents (245 DLE/SCLE, 51 SLE). activity and intensity in CLE Extensive skin lesions in CLE may be considered as a (see background information). prognostic marker for the further course of the disease. Dis- seminated DLE carries a higher risk of transition into SLE Monitoring: ↑ 100 % than localized DLE. Significantly increased ANA titers, an- Use of CLASI or RCLASI is sug- tibodies against extractable nuclear antigens (ENA) such as gested for monitoring thera- anti-Sm antibodies, newly emerging anti-ds-DNA antibo- peutic response. dies, increased ESR, proteinuria, hematuria, and arthritis are considered indicative for transition into SLE, particularly if Quality of life they occur simultaneously. Skin manifestations in CLE may result in severe distress, such as disfiguring, scarring, painful CLE lesions, mucous mem- Conflict of interest branes lesions, or alopecia. This in turn reduces patients’ Please refer to the long version of this guideline at www. quality of life. There is currently no disease-specific method awmf.org. © 2021 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft. | JDDG | 1610-0379/2021/1908 1244  16100387, 2021, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ddg.14492 by CochraneItalia, Wiley Online Library on [24/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Guideline S2k guideline: Cutaneous lupus erythematosus – Part 1 Correspondence to 13 Kuhn A, Wenzel J, Weyd H. Photosensitivity, apoptosis, and cytokines in the pathogenesis of lupus erythematosus: a critical review. Clin Rev Allergy Immunol 2014; 47: Prof. Dr. med. Margitta Worm 148–62. Department of Dermatology, Venereology and Allergology 14 Liu Z, Davidson A. Taming lupus-a new understanding of Charité – Universitätsmedizin Berlin pathogenesis is leading to clinical advances. 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