S2k guideline: Diagnosis and management of cutaneous lupus erythematosus – Part 1: Classification, diagnosis, prevention, activity scores

JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 19, Issue 8 p. 1236-1247 GuidelineOpen Access S2k guideline: Diagnosis and management of cutaneous lupus erythematosus – Part 1: Classification, diagnosis, prevention, activity scores Margitta Worm, Corresponding Author Margitta Worm margitta.worm@charite.de Department of Dermatology, Venereology and Allergology, Division of Allergology and Immunology Charité – Universitätsmedizin Berlin, corporate member of Free University of Berlin, Humboldt University of Berlin, and Berlin Institute of Health Correspondence to Prof. Dr. med. Margitta Worm Department of Dermatology, Venereology and Allergology Charité – Universitätsmedizin Berlin Charitéplatz 1 10117 Berlin E-mail: margitta.worm@charite.deSearch for more papers by this authorMiriam Zidane, Miriam Zidane Department of Dermatology, Venereology and Allergology, Division of Evidence-Based Medicine Charité – Universitätsmedizin Berlin, corporate member of Free University of Berlin, Humboldt University of Berlin, and Berlin Institute of HealthSearch for more papers by this authorLisa Eisert, Lisa Eisert Department of Dermatology and Venereology, Vivantes Klinikum Neukölln, BerlinSearch for more papers by this authorRebecca Fischer-Betz, Rebecca Fischer-Betz Clinic and Functional Division for Rheumatology, University Hospital Düsseldorf, DüsseldorfSearch for more papers by this authorIvan Foeldvari, Ivan Foeldvari Hamburg Center for Pediatric and Adolescent Rheumatology, HamburgSearch for more papers by this authorClaudia Günther, Claudia Günther Department of Dermatology, University Hospital Carl Gustav Carus Dresden, and Technical University of Dresden, DresdenSearch for more papers by this authorChristof Iking-Konert, Christof Iking-Konert III. Medical Clinic and Polyclinic, Section Rheumatology, University Hospital Hambug-Eppendorf, HamburgSearch for more papers by this authorAlexander Kreuter, Alexander Kreuter Dermatology, Venereology and Allergology, Helios St. Elisabeth Hospital Oberhausen, and University of Witten-Herdecke, OberhausenSearch for more papers by this authorUlf Müller-Ladner, Ulf Müller-Ladner Department of Rheumatology and Clinical Immunology, Kerckhoff Hospital GmbH, Bad NauheimSearch for more papers by this authorAlexander Nast, Alexander Nast Department of Dermatology, Venereology and Allergology, Division of Evidence-Based Medicine Charité – Universitätsmedizin Berlin, corporate member of Free University of Berlin, Humboldt University of Berlin, and Berlin Institute of HealthSearch for more papers by this authorFalk Ochsendorf, Falk Ochsendorf Department of Dermatology, Venereology and Allergology, University Hospital Frankfurt, Frankfurt am MainSearch for more papers by this authorMatthias Schneider, Matthias Schneider Clinic and Functional Division for Rheumatology, University Hospital Düsseldorf, DüsseldorfSearch for more papers by this authorMichael Sticherling, Michael Sticherling Dermatological Department, University Hospital Erlangen, ErlangenSearch for more papers by this authorKlaus Tenbrock, Klaus Tenbrock Department of Pediatrics and Adolescent Medicine, University Hospital RWTH Aachen, AachenSearch for more papers by this authorJörg Wenzel, Jörg Wenzel Dermatological Department, University Hospital Bonn, BonnSearch for more papers by this authorAnnegret Kuhn, Annegret Kuhn Medical Director, Hospital Passau, Passau, University of Münster, Münster, Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Center, Amsterdam, NiederlandeSearch for more papers by this author Margitta Worm, Corresponding Author Margitta Worm margitta.worm@charite.de Department of Dermatology, Venereology and Allergology, Division of Allergology and Immunology Charité – Universitätsmedizin Berlin, corporate member of Free University of Berlin, Humboldt University of Berlin, and Berlin Institute of Health Correspondence to Prof. Dr. med. Margitta Worm Department of Dermatology, Venereology and Allergology Charité – Universitätsmedizin Berlin Charitéplatz 1 10117 Berlin E-mail: margitta.worm@charite.deSearch for more papers by this authorMiriam Zidane, Miriam Zidane Department of Dermatology, Venereology and Allergology, Division of Evidence-Based Medicine Charité – Universitätsmedizin Berlin, corporate member of Free University of Berlin, Humboldt University of Berlin, and Berlin Institute of HealthSearch for more papers by this authorLisa Eisert, Lisa Eisert Department of Dermatology and Venereology, Vivantes Klinikum Neukölln, BerlinSearch for more papers by this authorRebecca Fischer-Betz, Rebecca Fischer-Betz Clinic and Functional Division for Rheumatology, University Hospital Düsseldorf, DüsseldorfSearch for more papers by this authorIvan Foeldvari, Ivan Foeldvari Hamburg Center for Pediatric and Adolescent Rheumatology, HamburgSearch for more papers by this authorClaudia Günther, Claudia Günther Department of Dermatology, University Hospital Carl Gustav Carus Dresden, and Technical University of Dresden, DresdenSearch for more papers by this authorChristof Iking-Konert, Christof Iking-Konert III. Medical Clinic and Polyclinic, Section Rheumatology, University Hospital Hambug-Eppendorf, HamburgSearch for more papers by this authorAlexander Kreuter, Alexander Kreuter Dermatology, Venereology and Allergology, Helios St. Elisabeth Hospital Oberhausen, and University of Witten-Herdecke, OberhausenSearch for more papers by this authorUlf Müller-Ladner, Ulf Müller-Ladner Department of Rheumatology and Clinical Immunology, Kerckhoff Hospital GmbH, Bad NauheimSearch for more papers by this authorAlexander Nast, Alexander Nast Department of Dermatology, Venereology and Allergology, Division of Evidence-Based Medicine Charité – Universitätsmedizin Berlin, corporate member of Free University of Berlin, Humboldt University of Berlin, and Berlin Institute of HealthSearch for more papers by this authorFalk Ochsendorf, Falk Ochsendorf Department of Dermatology, Venereology and Allergology, University Hospital Frankfurt, Frankfurt am MainSearch for more papers by this authorMatthias Schneider, Matthias Schneider Clinic and Functional Division for Rheumatology, University Hospital Düsseldorf, DüsseldorfSearch for more papers by this authorMichael Sticherling, Michael Sticherling Dermatological Department, University Hospital Erlangen, ErlangenSearch for more papers by this authorKlaus Tenbrock, Klaus Tenbrock Department of Pediatrics and Adolescent Medicine, University Hospital RWTH Aachen, AachenSearch for more papers by this authorJörg Wenzel, Jörg Wenzel Dermatological Department, University Hospital Bonn, BonnSearch for more papers by this authorAnnegret Kuhn, Annegret Kuhn Medical Director, Hospital Passau, Passau, University of Münster, Münster, Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Center, Amsterdam, NiederlandeSearch for more papers by this author First published: 13 August 2021 https://doi.org/10.1111/ddg.14492 AWMF registry no.: 013–060 Validity of this guideline: The guideline is valid until 24.03.2023. Professional Societies involved: – German Dermatological Society (Deutsche Dermatologische Gesellschaf, DDG) – German Society for Rheumatology (Deutsche Gesellschaft für Rheumatologie e.V. DGRh) – German Society for Pediatric Rheumatology (Gesellschaft für Kinder- und Jugendrheumatologie e.V., GKJR) AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Introduction Table 1 shows the terms and symbols used for the standardized representation of our recommendations. Table 1. Strengths of recommendation – wording, symbolism and interpretation (modified in accordance to Kaminski-Hartenthaler et al., 2014) Strength of recommendation Wording Symbol Strong recommendation in favor of an approach recommended ↑↑ Weak recommendation in favor of an approach suggested ↑ No recommendation as to approach may be considered 0 Recommendation against an approach not recommended ↓ Clinical introduction Cutaneous lupus erythematosus (CLE) is a rare, inflammatory autoimmune skin disease with heterogeneous clinical appearance. Currently, there is no treatment specifically approved for this disease. Topical and systemic medications are used off label. The goal of this guideline is to provide consensus-based recommendations on the diagnostics and treatment of patients with CLE, siehe Kommentar in accordance with the existing German S1 guideline from 2009 [1] and with the European S2K guideline [2]. Diagnostik und Therapie des kutanen Lupus erythematodes, AWMF-Register-Nr.: 013-060, 2020, www.awmf.org Classification, pathophysiology, and epidemiology Classification Lupus erythematosus (LE) is a heterogeneous, inflammatory autoimmune disease which can involve many organs with a variable course [3]. Systemic lupus erythematosus (SLE) must be differentiated from cutaneous lupus erythematosus (CLE). This guideline only covers the disease of CLE, even though in the literature CLE may not always be differentiated from cutaneous lesions associated with SLE [4]. The classification of the various skin manifestations of CLE is originally based on the work of James N. Gilliam who differentiated between LE-specific and non-LE-specific cutaneous lesions according to histological criteria [5]. LE-specific cutaneous manifestations (cutaneous lupus erythematosus, CLE) are further differentiated based on clinical, histopathological, serological, and genetic findings. This was modified and presented in the “Düsseldorf Classification” in 2004 (Table 2) [6, 7]. Examples of non-LE-specific cutaneous lesions that may quite frequently be associated with SLE include vascular skin disorders (periungual teleangiactasia, livedo racemosa, thrombophlebitis, Raynaud phenomenon). Table 2. Duesseldorf Classification of lupus erythematosus, modified in accordance to [1, 6, 7] Acute cutaneous lupus erythematosus (ACLE) Subacute cutaneous lupus erythematosus (SCLE) Chronic cutaneous lupus erythematosus (CCLE)– Discoid lupus erythematosus (DLE)– Chilblain lupus erythematosus (CHLE)– Lupus erythematosus profundus/panniculitis (LEP) Intermittent cutaneous lupus erythematosus (ICLE)– Lupus erythematosus tumidus (LET) Tables 3 and 4 summarize the clinical appearance and special characteristics of the various forms of chronic CLE (CCLE) and the intermittend CLE (ICLE). The clinical signs and special characteristics of acute CLE (ACLE) and subacute CLE (SCLE) can be found in the supplement. Table 3. Chronic cutaneous lupus erythematosus (CCLE), according to [1] Discoid lupus erythematosus (DLE) Clinical appearance ▸ Localized type (ca. 80 %) – Face and capillitium ▸ Disseminated type (about 20 %, frequently associated with SLE) – Also upper trunk and extensor sides of limbs ▸ DLE of the oral mucous membranes – Buccal mucous membranes >> palate Special characteristics ▸ Most common type of CCLE ▸ Discoid erythematous plaques with tightly adhering follicular hyperkeratoses and hyperesthesia ▸ Manual removal of keratosis (“carpet tack sign”) is painful ▸ Active margin with erythema and hyperpigmentation ▸ Scarring with central atrophy and hypopigmentation, scarred alopecia in hirsute areas ▸ Discoid lesions in the lip area > buccal mucous membranes ▸ Mutilations in the area of nose and mouth, vermicular perioral scarring ▸ Provocation by irritant stimuli (Koebner’s phenomenon) may occur ▸ In rare cases, squamous cell carcinoma may develop in healed scars ▸ ANA with high titers (rarely, in ca. 5 %), usually no anti-ds-DNA antibodies, rarely antibodies against Ro/SSA or U1-RNP ▸ In 10 % of cases, DLE is the first sign of SLE Lupus erythematosus profundus (LEP; Synonym: LE panniculitis) Clinical appearance and special characteristics ▸ Subcutaneous, nodular or discoid, firm infiltrations, with secondary adherence to the overlaying skin ▸ Surface of the lesions: inflammatory erythema, no alteration, or simultaneous DLE ▸ Predilection sites: Gluteal or hip area, thighs, upper arms, face, chest ▸ In rare cases, periorbital edema may occur as an initial sign ▸ Ulceration and calcification may occur ▸ Healing may result in scars and deep lipatrophy ▸ ANA positive in up to 75 %; usually no anti-ds-DNA antibodies, occurrence of anti-ds-DNA antibodies may signify transition into SLE ▸ ACR criteria from 1982 are formally fulfilled in 35–50 %, association with SLE is more rare Chilblain lupus erythematosus (CHLE) Clinical appearance and special characteristics ▸ Livid swellings that are painful on pressure, as well as large, cushion-like nodes, partly with central erosion and ulceration ▸ Predilection sites: symmetrical acral areas exposed to the cold (dorsal and marginal regions of the fingers, tips of the toes, heels, ears, nose) ▸ EIGENER PUNKT: Occurrence in the cold and damp seasons or after a drop in temperature ▸ Clinical and histological differentiation from genuine chilblains (perniones) is difficult ▸ ANA, anti-Ro/SSA antibodies and positive rheumatoid factors are variable; usually no anti-ds-DNA antibodies ▸ Associated with SLE in about 20 % ▸ Familial “Chilblain lupus”: First description of a monogenic, inherited form of CLE Table 4. Intermittent cutaneous lupus erythematosus (ICLE), according to [1] Lupus erythematosus tumidus (LET)Clinical appearance ▸ Succulent, indurated, urticaria-like erythematous plaques with smooth surface without involvement of the epidermis ▸ Lesions are often arranged in annular or sometimes semicircular patterns ▸ Predilection sites: areas exposed to light (especially face, upper trunk, cleavage, extensor sides of the arms) ▸ Healing without scars or pigment disorders Special characteristics ▸ Pronounced photosensitivity (in > 70 % positive photoprovocation test with UVA and/or UVB) ▸ ANA in 10–30 % positive, anti-Ro/SSA and anti-La/SSB antibodies in about 5 % ▸ Varying course with very good prognosis, spontaneous remission may occur Pathophysiology CLE is a cutaneous autoimmune disease with simultaneous activation of the innate and adaptive immune system [8, 9]. Depending on the patient’s individual genetic disposition, and to some extent via immunostimulatory triggers (i.a. UV rays), an autoimmune response against the own epidermis occurs [10-12]. The histological correlation of this specific anti-epidermal inflammation is the so-called interface dermatitis. This is characterized by infiltration of the basal epidermal layer with cytotoxic lymphocytes and plasmacytoid dendritic cells (pDC), but also cell death of local keratinocytes. Based on the CLE subtype and the individual patient, different effector mechanisms of the immune system are involved. These include the adaptive immune response (mainly auto antibodies, T cells) as well as the innate immune response with activation of cell death, cytokine, and DAMP (damage-associated molecular pattern) pathways. Central pro-inflammatory factors include type I/III interferons and associated cytokines (mainly CXCL10) which are expressed both by pDC and keratinocytes, and are required for the recruitment of CXCR3+ effector cells [13]. A key to understanding the development of skin lesions in CLE is that factors from the adaptive immune system (which is actually downstream) can trigger pathways of the (primary) innate immune system, resulting in a “permanently activated short circuit” [14]. Epidemiology Due to the various subtypes, there is only a limited amount of valid data on the prevalence of CLE. Transition from CLE to SLE has been reported for 20 % of CLE patients within three to five years [15-18]. Up to 30 % of all CLE patients develop more than one subtype [17, 18]. CLE usually appears during the third to fourth decade of life, and the females to males gender ratio is much lower than with SLE (3 : 1 to 3 : 2) (9 : 1) [19, 20]. In three quarters of all patients with SLE, skin lesions develop during the course of the disease, and in one quarter the skin is even the initial manifestation. A Swedish publication puts the incidence of CLE at 4.0 per 100,000 [21]. Within the subtype of CCLE, discoid lupus erythematosus (DLE) is the most common form at 80 % [21]. DLE is most common in African Americans, while SCLE occurs predominantly in light-skinned European ethnicities. Chilblain LE (CHLE) and LE tumidus (LET) are found mostly in Europe [22-25]. Diagnostics Diagnostics Diagnostics of CLE should be based on the clinical and histological findings. Patients with CLE without systemic involvement often lack detectable autoantibodies, but if present the autoanti-bodies may help to support the diagnosis and to better assess the prognosis [4]. Histology If CLE is suspected, the diagnosis should always be confirmed via skin biopsy (except in cases of ACLE if SLE has already been confirmed). Ideally, the specimen should be obtained from an active, non-treated lesion. Active lesions typically show interface dermatitis with anti-epidermal lymphocytic infiltration, vacuolization of basal keratinocytes, and colloid bodies [26, 27]. Acanthosis, dermal infiltrations, and mucin deposits may vary depending on the CLE subtype (Table 5). Table 5. Prominent histological and immunohistological characteristics of lesions from cutaneous lupus erythematosus (CLE), modified in accordance to [11] Subtypes Histology/Immunohistology CLE ▸ Interface dermatitis ▸ Hydropic degeneration of the basal epidermis ▸ Lymphoid infiltration (mostly plasmacytoid dendritic cells and T cells) ▸ Dermal mucin deposits ▸ Strong expression of chemokines regulated by interferons (MxA, CXCL10) ACLE ▸ Discrete infiltrations with moderate interface dermatitis ▸ Sporadic neutrophils in the infiltrations as well as nuclear detritus SCLE ▸ Interface dermatitis with few cells and cutaneous, perivascular infiltrations ▸ Moderate mucin deposits Special stains Special stains may help to confirm the diagnosis of CLE but are not obligatory. Some examples are alcian blue stains (dermal mucin deposits), PAS stains (basal laminae) [27], and detection of plasmacytoid dendritic cells (BDCA2, CD123) [28]. Surrogate markers of IFN activation (MxA) can visualize activation of the innate immune system within the lesion, which is characteristic for CLE [29]. Direct immunofluorescence Direct immunofluorescence (DIF) can show lesional granular deposits of C3 as well as IgG and IgM in CLE. In uncertain cases, this test can help confirm the diagnosis of LE [26, 27, 30]. It should be noted that false-positive results may occur in skin areas exposed to light, especially in rosacea [31]. Non-lesional skin not exposed to light may show a higher number of positive DIF in SLE patients (lupus band) [30, 32]. However, the authors would like to stress that this test is insufficient to confirm the diagnosis of SLE, which must always be correlated with the clinical findings. Recommendation Strength Agreement A lesional biopsy is recommended for histological confirmation of a clinical of CLE diagnosis. Exceptions can be made in cases of ‘butterfly rash’ and/or mucosal lesions. ↑↑ 100 % Special stains as well as immunohistology are suggested to confirm diagnosis (examples include PAS, alcian blue, CD123, MxA). ↑ 100 % Direct immunofluoresence (DIF) is suggested in cases where differential diagnosis is difficult. Analysis of lesions not exposed to light is recommended. ↑↑↑ 100 % Direct immunofluoresence (DIF) of non-lesional skin exposed to light is not recommended. ↓ 100 % Photoprovocation Photoprovocation with UV light according to a standard protocol is appropriate for confirming the diagnosis of photosensitive CLE subtypes [33]. After UV exposure, specific CLE lesions will only appear after a latency of 8 ± 4.6 days and will then persist for a considerable time. In contrast, other photodermatoses such as polymorphous light eruption (PLE) will appear much earlier after UV exposure and the lesions will subsequently resolve. In addition to the clinical evaluation, UV-induced CLE lesions can be confirmed via biopsy [33]. Recommendation Strength Agreement In special cases, standardized photoprovocation performed by experienced investigators is suggested (for example to exclude CLE, or to differentiate between CLE and polymorphous light eruption). ↑ 100 % Classification criteria of SLE A working group from the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) has developed a scoring system for classification of SLE [34, 35] (Table 6). This has replaced the former ACR criteria (established in 1982, revised in 1997) and the SCLICC criteria (Systemic Lupus Erythematosus Collaborating Clinics Group, established in 2012) [34]. These two scores put equal emphasis on serological and clinical criteria. So far, four out of eleven criteria ACR criteria from 1982 contained mucocutaneous manifestations (butterfly rash, discoid lesions, light sensitivity, and oral ulcerations). Light sensitivity, in particular, can easily be interpreted differently, resulting almost certainly in over-estimation of SLE prevalence [4]. It has been shown that about 50 % of SLE patients, 10 % of DLE patients, and practically all ACLE patients will fulfill the criteria for SLE without necessarily having systemic (organ) involvement. The new criteria are designed for better differentiation between CLE and SLE [35]. Table 6. New EULAR/ACR SLE classification criteria, according to [35] Prerequisite ANA (HEp2-IFT) ≥ 1 : 80 (may vary depending on the normal range of the local laboratory) Basic conditions – If other causes are present, such as infection, neoplasia, medications, or other diseases, a criterion is not counted.– At least one criterion needs to be currently present.– Criteria are fulfilled if they have been present (documented) at any time.– Criteria do not have to be present simultaneously.– Within each domain, only the highest score is counted for the total score. Clinical domains and criteria Weighting Constitutional Fever 2 Skin Non-scarring alopecia 2 Oral ulcers 2 SCLE or DLE 4 ACLE 6 Arthritis Synovitis in ≥ 2 joints or pain on pressure in ≥ 2 joints with morning stiffness ≥ 30 minutes 6 Neurology Delirium 2 Psychosis 3 Seizures 5 Serositis Pleural or pericardial effusion 5 Acute pericarditis 6 Hematology Leukopenia 3 Thrombocytopenia 4 Autoimmune hemolysis 4 Kidneys Proteinuria > 0.5 g/24 h 4 Lupus nephritis (histol.) Type II, V 8 Lupus nephritis (histol.) Type III, IV 10 Immunological criteria Weighting Antiphospholipid AB aCL>40 GPL or aß2GPI>40 GPL or LA + 2 Complement Low C3 or C4 3 Low C3 and C4 4 Highly specific auto-antibodies Anti-ds-DNA AB 6 Anti-Sm AB Classification SLE classification: ≥ 10 points EULAR/ACR criteria: sensitivity 98 %, specificity 97 % Recommendation Strength Agreement Diagnosis:The use of the 2019 EULAR/ACR criteria is recommended in order to differentiate CLE from (Table 6). ↑↑ 100 % Monitoring:For any CLE patient, a reassessment of the 2019 EULAR/ACR criteria is suggested either once a year and/or in case of clinical/laboratory changes. ↑ 100 % Laboratory parameters In patients with ACLE (which is most frequently associated with SLE) and/or in patients with SCLE (frequently associated with arthritis or other moderate organ involvement), laboratory investigations should always be performed to exclude or confirm organ involvement. Laboratory investigations are, however, not only useful in initial diagnostics but also for evaluation of prognosis and activity. In addition, drug side effects need to be monitored. We cannot give evidence-based recommendations for the frequency of laboratory investigations – this depends on individual factors such as severity and activity of the (cutaneous) disease, treatment, comorbidities and their treatment, as well as previous findings (such as detection of ANA or ENA) and changes in laboratory values (such as anti-ds-DNA antibodies or complement). Table 7 offers a list of recommended blood analyses in patients with CLE, including their significance. Table 7. Recommended blood tests for patients with CLE and their relevance Test Remarks Blood count including differential blood count Hematological disorders (anemia, leukopenia or lymphopenia as well as thrombocytopenia) are 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 toxic side effect of drug treatment. ESR and CRP ESR is typically increased in SLE patients (due to hypergammaglobulinemia, among other reasons) 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 glomerular filtration rates (eGFR) according to a standardized formula, or (rarely nowadays) creatinine 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 sediment, and proteinuria Urinalysis is required to screen for renal involvement. In case of abnormal values, urinalysis should be repeated and the urine sediment investigated.The protein (or albumin) to creatinine ratio in morning urine can be used for screening or monitoring 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! Hepatic function: ASAT, ALAT, γGT and ALP, bilirubin if indicated Involvement of the liver in the sense of an overlap syndrome with autoimmune hepatitis (AIH) is rare in patients with CLE/SLE. Increased hepatic enzymes thus usually result from toxic side effects induced by medications (drug-induced liver injury [DILI]).Hepatic function should be monitored before and during medical treatment. Early consultation 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 investigation to exclude other disorders (monoclonal gammopathies, IgA deficiency, hyper-IgE syndrome). Antinuclear antibodies (ANA) (HEp-2 cell test) ANA determination is the classic screening test for connective tissue diseases and should be performed 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 [36].Positive ANA should be further specified via ENA. The frequency of ANA and ENA varies depending 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 monitoring disease courses and activity. Antiphospholipid AB (APS-AB) and lupus anticoagulant Antiphospholipid antibodies (APS-AB, most frequently cardiolipin, beta-2 glycoprotein, and the lupus anticoagulant) are included in the EULAR and ACR/SLICC criteria for SLE.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. Recommendation Strength Agreement In CLE patients, it is r