Lupus erythematosus systemic M32.9

Author: Prof. Dr. med. Peter Altmeyer

Co-Autors: Marcus Kuchner, Dr. Jenny-Lou Navarra

All authors of this article

Last updated on: 26.08.2023

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Synonym(s)

Butterfly lichen; late-onset-SLE; Lupus erythematosus integumentalis et visceralis; Lupus erythematosus visceralis; Skin rheumatism; SLE; System erythematodes; Systemic erythematosus; Systemic lupus erythematosus; visceral erythematodes; Visceral lupus erythematosus

Definition
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Inflammatory, heterogeneous, polyorganic autoimmune disease with variable disease course.

Diagnosis is based on pathological clinical symptoms of skin, joints, kidneys and central nervous system. Furthermore on serological (especially antinuclear antibodies against dsDNA) and further general inflammatory and immunohistological parameters (pathological: ESR, alpha2/gamma globulins, complement activation, anemia, LDH).

In the past, clinical diagnosis was performed according to the criteria of the ARA (American Rheumatism Association), which, however, do not adequately reflect the real clinical conditions and should be revised. Therefore, in 2012, a new classification was developed by the "Systemic Lupus International Collaberating Clinics - SLICC":

Clinical Criteria (SLICC Criteria - cited in Petri M et al. 2012):

  • Acute cutaneous lupus erythematosus (including butterfly erythema).
  • Chronic cutaneous lupus erythematosus (e.g., localized or generalized discoid lupus erythematosus)
  • Oral ulcers (palate or nose)
  • Non-scarring alopecia (or diffuse effluvium)
  • Synovitis or tenderness (2 or >2 joints) and morning stiffness (30 min or longer)
  • Serositis (pleurisy or pericardial pain lasting longer than 1 day)
  • Renal involvement (single urine: protein/creatinine ratio or protein in 24h collection urine, disc electrophoresis: proteinuria: >500mg/d or cylindruria).
  • Neurological involvement (e.g. epilepsy, psychosis, myelitis).
  • Hemolytic anemia
  • Leukopenia (<4,000/µl) or lymphopenia (<1,000/µl)
  • Thrombocytopenia (<100,000/µl)

Immunologic Criteria:

  • Chromatin-Ak
  • ANA titer above laboratory reference value
  • Anti-dsDNA antibody = anti-nDNA-Ak (ds=double stranded ⇔ n=native).
  • Anti-ssDNA-Ak ss= single stranded
  • Anti-histone-Ak
  • Anti-Sm antibody
  • Anti-phospholipid antibodies (anti-cardiolipin and anti beta2-glycoprotein antibodies, false positive VDRL).
  • Decreased complement (C3,C4, CH50)
  • Positive direct Coombs test

Evaluation; =/>4criteria (at least 1 clinical and 1 immunological) or confirmed lupus nephritis + positive ANA, anti-dsDNA (sensitivity 94%, specificity 92%).

Classification
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Systemic lupus erythematosus can be divided into 3 groups depending on the initial manifestation of the disease:

  • Juvenile-onset SLE (≤18 years): 18%
  • Adult-onset SLE (>18 - 50 years): 71%
  • Late-onset SLE(>50 years): 11%

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Occurrence/Epidemiology
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Prevalence: 36/100,000; incidence: 5-10/100,000.

In childhood, the prevalence is lower by a power of ten.

Depending on ethnicity, different frequencies can be observed, for example, systemic LE occurs 4 times more frequently in Africans than in Caucasians or Asians.

Etiopathogenesis
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Autoimmune disease, probably caused by genetically induced abnormalities of the immune system. This mainly affects the immunological recognition of "self" nucleic acids. Thus, virally induced IFN-α can initiate a dysregulation of the immune response, which on the one hand promotes antigen presentation via maturation and proliferation of myeloid dendritic cells and on the other hand leads to the development of autoantibodies via activation of autoreactive B cells.

These autoantibodies, typically directed against nucleic acids in SLE, form immune complexes with "self" nucleic acids from cell debris. On the one hand, the deposition of these immune complexes in the vessels initiates inflammatory processes. On the other hand, uptake of the immune complexes by plasmacytoid dendritic cells via TLR signaling cascades stimulates further interferon production. Thus, activation of the type I interferon (IFN) system appears to be the central pathogenic mediator in SLE. Cell signaling by all type I IFNs, including IFNα, IFNβ, IFNɛ, IFNκ, and IFNω, is mediated by the type I IFN-α/β/ω receptor (IFNAR), resulting in IFN-stimulated gene transcription. In this way, a vicious circle is created, leading to the breakdown of immunological tolerance and consequently to autoimmunity.

Consequently, the organism must have appropriate mechanisms that, on the one hand, ensure a prompt and efficient immune response to viral nucleic acids, but, on the other hand, protect against inadequate activation of the immune system by endogenous nucleic acids.

In a smaller proportion of patients, a mutation was detected in the TREX1 gene (3p21.31), a gene encoding an intracellular DNase (see Nucleases below) that plays an important role in apoptosis. Evidence suggests that increased apoptotic propensity and decreased clearance of apoptotic material represent an important pathogenetic principle of SLE.

Other genes associated with SLE are: FCGR2A (1q23.3/ lupus nephritis), FCGR2B (1q23.3), CTLA4 (2q33.2), DNASE1 (16p13.3).

Complement deficiency: The incidence of SLE in patients with C1q, C4 or C2 deficiency is 90%, 75% and about 15%, respectively.

Triggering factors are considered to be:

  • UV irradiation(induce apoptosis)
  • Drugs (antihypertensives, procainamide, anticonvulsants, INH, antibiotics, antifungals e.g. terbinafine, oral anticonceptives, thiazide diuretics, NSAIDs, atorvastatin)
  • traumas, psychological stress, gravidity
  • Systemic underlying diseases such as: tuberculosis, hepatitis, renal diseases.
  • Silicosis: a two- to eight-fold risk of rheumatoid arthritis and systemic lupus erythematosus was found in this group of individuals (further, a more than 24-fold risk of systemic scleroderma and ANCA+ vasculitis) (Makol A et al. 2011).
  • B cell defects: there is evidence that B cells from patients with systemic lupus erythematosus have a reduced regulatory capacity compared to CD4+T cells (see regulatory B cell below) and this is independent of their origin.
  • Regulatory T cells (Treg): these also play an important role in the prevention of autoimmune diseases in a healthy organism.

Manifestation
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Occurring mainly in younger adults.

Ratio of females to males (w:m) is 4:1.

The so-called "late onset SLE" occurs after the age of 50 (w:m=2:1).

Juvenile onset SLE occurs at an average age of 12 years (w>m; incidence 0.9/100,000/year); preferred in African Americans; less common in Caucasians.

Clinical features
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  • General symptoms are detectable in 95% of SLE patients: fever, weakness, weight loss, arthralgias.
  • Other organ changes: polyarthritis, 50-65% of SLE patients have kidney involvement (lupus nephritis, nephrotic syndrome), lymph node swelling, wet pleurisy (40-60%), less frequently lupus pneumonitis or pulmonary fibrosis, hepatosplenomegaly, endo and/or pericarditis(Libman-Sacks syndrome) and myocarditis with consecutive dilated cardiomyopathy. Furthermore: polymyositis, peritonitis, gastritis, colitis and mostly unspecific neurological symptoms (15-20%) like headache, cognitive impairment, psychosis and depression but also brain-organic symptoms like seizures and transverse myelitis.
  • Skin lesions are present in about 75% of patients. They are initial symptoms of the disease in about 25% of patients.
  • Skin lesions can be divided into frequent and less frequent, and specific and non-specific (lupus-associated) skin lesions:
    • Frequently Present Specific HV:
      • "Butterfly erythema": Persistent, blurred, butterfly-like erythema on the face.
      • Morbilliform, scarlatiniform, multiforme, extensive (rosacea- or livedo-like) or bullous exanthema (especially upper back and chest areas).
      • Localized, pityriasiform, firmly adherent scaling or spatter-like atrophies.
      • With increasing duration of the erythema, two-dimensional livid-red plaques develop (especially in the late-onset type), preferably in the anterior chest area and also on the shoulders and hands and fingers. In the plaques, flat (sometimes painful) keratoses, spatter-like whitish atrophies, telangiectasias, erosions with crusts develop. Overall, a poikilodermic clinical picture may develop (see Fig.).
      • Localized, patchy or diffuse erythema and plaques especially on finger and toe extremities.
      • Chilblain's lupus (chilblain = frostbite) are pressure-dolent plaques that occur primarily with exposure to cold and affect mainly the acras.
    • Less frequently present specific HV:
    • Associated (non-specific) HV:
  • Mucosal changes: Edematous, livid enanthema of the oral mucosa with planar, even extensive erosions and ulcerations, especially on the hard palate and buccal mucosa. Exudative, crusted cheilitis tending to atrophy.
  • Drug-induced lupus, which is less severe, is usually limited to the following symptoms: polyarthritis, pleurisy/pericarditis; no CNS or kidney involvement, still ANA+, often anti-histone antibodies, usually no anti-DNA antibodies!
  • To assess activity and damage of mucocutaneous manifestations, the CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) was developed and validated.

Laboratory
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  • Non-specific activity symptoms:
    • ESR elevation (often correlates with severity of disease phase), CRP elevated.
    • Often antibody-induced cytopenias: leukopenia, neutropenia, left shift, lymphopenia, eosinopenia, thrombocytopenia, macrocytic anemia.
    • Reticulocytes and LDH elevated.
    • Signs of complement activation (decrease in C3 and C4 or CH50).
    • Electrophoresis: hypalbuminemia, hypergammaglobulinemia.
    • Cryoglobulins, circulating immune complexes possible.
    • In 33% of cases false positive rheumatoid factor, but false negative rheumatoid factor is also possible, Coombs test frequently positive.
    • In 25% of cases false-positive syphilisserology (VDRL)
    • Calreticulin-Ak: The significance of these antibodies against this chaperone protein has not yet been clarified.
  • Specific activity symptoms:
    • ANA: positive to 95% (high titer) - titer does not correlate with disease acuity!
    • Anti-dsDNA-Ak: positive up to 70%. Titers correlate with activity (note: usually the decrease of complement factors goes parallel to the increase of titers).
    • Anti-Sm -Ak: positive up to 30%.
    • Anti-Ro-Ak (SSA): positive up to 25%. Increased titers of SSA (mostly in combination with SSB) are found mainly in LE patients with increased photosensitivity.
    • Anti-C1q-Ak: correlates with disease activity
    • U1-RNP antibodies
    • Phospholipid antibodies (positive to 35%).
    • Urine: proteinuria, haematuria and cylindruria depending on renal involvement.

Antinuclear antibodies (homogeneous, speckled, peripheral or nucleolar pattern), antibodies against defined cell nuclear components (double-stranded and single-stranded DNA antibodies, RNA, ENA, Sm antibodies), anticytoplasmic antibodies (mitochondria, ribosomes, proteins), antibodies against blood cells (erythrocytes, T and B lymphocytes, platelets). 30-50% of patients have antiphospolipid AK. These can cause thromboembolic complications, which can be interpreted as a consequence of a phospholipid antibody syndrome. See also Autoantibodies.

Notice. Drug-induced lupus erythematosus frequently shows H1 and H3 histone antibodies. Otherwise, histone antibodies do not play a significant role in the DD of autoimmune diseases.

Histology
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Interface dermatitis, usually much less prominent than in lupus erythematosus integumentalis. Discrete perivascular lymphocytic infiltrate with oedema of varying severity (depending on the acuteity) in the upper dermis with a blurred dermo-epidermal junction zone. Focal epidermotropy with vacuolar degeneration of the basal keratinocytes.

Direct Immunofluorescence
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Lupus band test: Granular immunoglobulin deposits on the basement membrane (IgG, IgM,C3, IgA); also in healthy skin (especially positive for sun exposure in up to 80% of cases). The value of the lupus band test has been increasingly questioned in the past. In larger studies, however, it could be shown that the disease activity (DNA-AK titer and kidney involvement higher than in the control group) was higher in positive lupus band tests than in negative ones.

General therapy
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The treatment of SLE is based on few randomized controlled trials. Personal expertise over many years is therefore an important prerequisite for adequate therapy.

External therapy
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Light protection: Consistent light protection is advisable with light protection preparations with high protection in the UVA and UVB range. Consequence for the professional as well as leisure behaviour e.g. also for the choice of holiday destinations. No sunbathing!

Internal therapy
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  • Stage-appropriate interdisciplinary (basic) therapy. Apart from basic therapy, organ manifestations (e.g., renal involvement) should be treated in a specialist manner.
    • Antimalarials: In patients without organ-dangerous manifestations (skin-joint pleurisy), monotherapy with antimalarials should be sufficient in the long term. Initially, these are combined with nonsteroidal anti-inflammatory drugs and/or glucocorticoids (see below). It should be possible to reduce the glucocorticoid dose to 5.0-7.5 mg (prednisolone equivalent) under this theapy regime. If this is not possible the use of immunosuppressants is indicated.
      • Chloroquine (e.g. Resochin) or alternatively hydroxychloroquine (e.g. Quensyl) have a firm place in the basic therapy for mild forms of SLE with predominant joint and skin involvement in combination with a low prednisolone dose(continuous therapy up to max. 7.5 mg/day p.o.). Initial therapy with chloroquine 6.0-6.5mg/kgKG p.o., after 2 weeks reduction to 250 mg/day. Hydroxychloroquine is given at a dosage of 3.5-4.0 mg/kgKG /day p.o. for 4 weeks.
      • In case of resistance, mepacrine can be given in combination with chloroquine or hydroxychloroquine. In exceptional cases, in case of intolerance to chloroquine or hydroxychloroquine also as monotherapy. The mepacrine daily dose of 100 mg/day should not be exceeded,if necessary reduction to 25-50 mg /day in case of side effects. Improvement of skin findings occurs after 3 to 4 weeks, maximum effect after 6 to 8 weeks.
    • Glucocorticoids: Prednisolone (e.g. Decortin H) is generally accepted as the standard treatment of choice for basic medication. The amount of initial dose depends on disease activity.
    • Mild disease manifestation (skin, musculoskeletal, Raynaud's): Peroral application of 0.25-0.5 mg/kg bw as a single morning dose.
    • Moderate disease manifestation (skin, musculoskeletal, leukopenia, discrete renal involvement, mild pleuropericarditis): 0.5-1.0 mg/kg bw divided into 2-3 ED (e.g., 50-25-0 or 50-25-25 mg p.o.).
    • Severe disease manifestation (severe lupus nephritis, CNS involvement, pleuropericarditis, necrotizing vasculitis): 8-hourly administration of 100 mg methylprednisolone i.v., initial dose may be increased to 250 mg. Alternatively, pulse therapy with 500-1000 mg/day i.v. as a single dose. For dose reduction, reduce evening and midday dose rather than morning dose. Above a total dose of 25 mg/day, further reduction in the form of the "alternate day" mode, e.g., 25 and 20 mg or 25 and 15 mg alternated daily. As a maintenance dose, 10 and 5 mg should be aimed for.
    • Azathioprine (e.g. Imurek): Generally accepted as standard treatment for moderate and severe forms (in case of insufficient response to combination antimalarial/prednisolone therapy - prednisolone dose cannot be lowered below 10 mg). Initial dose with 2-3 mg/kg bw p.o. dose is distributed to 2-3 ED. Onset of action after 3-4 weeks.
    • Notice. The use of azathioprine leads to glucocorticoid savings!

    • Alternative: Methotrexate (e.g. MTX): 10-20 mg/week p.o. Especially indicated in forms of SLE with pronounced joint manifestations. No effect in severe renal or CNS involvement. Since the immunosuppressive effect of methotrexate differs from its cytostatic effect (inhibition of dihydrofolate reductase), administration of 5-10 mg/week p.o. folic acid (e.g. folan) offset by 2 days from methotrexate administration.
    • Alternative: Mycofenolate mofetil 1.0 g/2 times/day p.o in combination with prednisolone p.o. (dosages see above).
    • Alternative: Cyclophosphamide (e.g. Endoxan): 1-2 mg/kg bw/day p.o. or 1000 mg i.v. every 4 weeks. Onset of action after about 1 week. High teratogenic effect. Use only in severe and life-threatening courses. Only in severe lupus nephritis together with prednisolone therapy of 1st choice. Weekly blood count checks. Therapy duration with oral administration 4-6 weeks, then 1 week therapy break, then 3-week therapy, followed by a 1-week therapy break each time. Max. Therapy duration 6-10 months.
    • Alternative: Ciclosporin A (e.g. Sandimmun): Appears to have a beneficial effect on SLE. Dose recommendations are 3-5 mg/kg bw/day divided over 2 EDs. Optimal blood level is 100-200 mg/ml blood (determination possible in specialized laboratories). Its use is limited by nephrotoxicity and hepatotoxicity and by hypertension.
    • Alternative: plasmapheresis (or immunoadsorption): Therapeutic approach to eliminate circulating immune complexes and autoantibodies. Currently still controversial, beneficial effects have been described in some studies.
    • Alternative: Immunoglobulins (see also IVIG): Indicated as high-dose therapy (IgG infusions, e.g. Intratect 400 mg/kg bw on 3-5 days) when marked leukopenia (especially granulocytopenia with frequent infections) or thrombocytopenia does not allow the use of antimetabolites or alkylants.
    • Alternative: Belimumab (Benlysta): Human IgG1λ monoclonal antibody that shortens the lifespan of CD20+ B lymphocytes and plasma cells.... Belimumab thus has a selective immunosuppressive effect. It is approved for the treatment (add-on therapy) of adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE). 2 phase III studies with a total of 684 patients are available. The value of this treatment remains to be seen.
    • Complementary: granulocyte colony-stimulating factor (e.g. Neupogen): Has been shown to be effective in lupus-associated leukopenia; dosage: 30 μg/day s.c. for 1-3 days.
    • Supplementary: Anakinra (Kineret): Based on single case reports, well effective in patients with lupus arthritis ( off-label use). 1 time/day 100 mg s.c. in combination with methotrexate. Alternatively, anakinra can be combined with leflunomide (Arava).
    • A smaller study exists on tocilizumab. Significant improvement was seen in disease activity of SLE in 8 of 15 pat. Arthritis improved in 7 pat. DNA-AK levels reduced, as did IgG levels.

Progression/forecast
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Often begins in puberty. At first manifestation < 5 years a rare monogenic form must be considered. A relapsing course is typical. Prognosis quoad vitam depending on organ involvement. In the first years of the disease, bacterial infections (e.g. also by immunosuppressive therapy) contribute to mortality. After a longer period of the disease, cardiovascular complications determine the mortality rate. The five-year survival rate with appropriate therapy is > 90%. Ten-year survival rate: 92%.

Tables
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Diagnostic criteria of the American Rheumatoid Association (ARA) [also ACR criteria (American College of Rheumatology)] for systemic lupus erythematosus

Butterfly erythema: At the level of the skin or raised, with recess of the nasolabial folds.

Discoid foci with adherent keratotic scaling and follicular keratoses, atrophic scarring in old foci.

Light sensitivity (photosensitivity).

Usually painless oral or nasopharyngeal ulceration.

Non-erosive arthritis affecting 2 or more joints, with pain, swelling or effusion.

Serositis, pleuritis, pleural rubbing or pleural effusion, pericarditis, pericardial rubbing or pericardial effusion.

Kidney involvement: Persistent proteinuria (> 0.5 g/day or > 3 +, cell cylinders - erythrocytes, tubule cells, etc.).

Neurological involvement: Seizures in the absence of other clear causes (such as drugs or metabolic disorders); psychosis in the absence of other causes (such as drugs or metabolic disorders).

Hematological disorders: Hemolytic anemia with reticulocytosis; leukopenia < 4,000/μl; thrombocytopenia < 100,000/μl.

Immunological symptoms: elevated anti-DNA titre; detection of Sm-nuclear antigen; detection of antiphospholipid antibodies; biologically false positive syphilisserology (> 6 months).

Antinuclear antibodies, unrelated to a drug which may be associated with a so-called drug-induced lupus syndrome.

Test site

Shoulder and upper back

Test Fields

5 x 8 cm

Radiation sources

Metal halide lamps (340-400 nm)

UV-B: Fluorescent lamp (e.g. Philips TL 12; 285-350 nm)

Radiation doses

UV-A: 3-4 x 60-100 J/cm2

UV-B: 3-4x 1.5x MED

Reading

24, 28, 72 hours and 1, 2, 3 weeks after radiation

Note(s)
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  • Smoking is strictly prohibited. Risk of aggravating the vascular symptoms.
  • Further reduction of cardiovascular risks: Optimal antihypertensive therapy. This setting is also important for maintaining renal function.
  • Osteoporosis prophylaxis: calcium-rich nutrition/supplementation+Vit D3
  • SLE and pregnancy: SLE is not associated with reduced fertility. Pregnancy can increase inflammatory activity. Competent care by gynaecologists is important.
  • SLE and anticonception: Oestrogen-containing anticonceptives have been characterized at times as relapsing. Recent studies could not confirm this. Absolute contraindication of estrogens exists in the case of proven antiphospholipid antibodies and nicotine abuse.
  • Notice! Visceral lupus erythematosus is associated with an increased risk of vasculitis and thrombosis!

  • Pregnancies and systemic LE are controversially discussed. Exacerbations are expected in 30-60% of patients. In particular, nephrological monitoring should be performed in patients who already had renal problems before the onset of pregnancy.

  • If pregnancy has occurred, basic therapy with hydroxychloroquine should be continued. Also azathioprine and cyclosporine with strict indication (see also neonatal lupus erythematosus)

  • Vaccination recommendations under http://dgrh.de/Impfmpfehlung.html

Literature
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  10. Makol A et al (2011) Prevalence of connective tissue disease in silicosis (1985-2006)-a report from the state of Michigan surveillance system for silicosis. Am J Ind Med 54:255-262.
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  14. Rothenberg RJ et al (1988) The use of methotrexate in steroid-resistant systemic lupus erythematosus. Arthritis Rheum 31: 612-615
  15. Wagner J et al (1991) Contraceptives and systemic lupus erythematosus. Dermatologist 42: 726
  16. Williams WW et al (2005) A 29-year-old pregnant woman with nephrotic syndrome and hypertension. N Engl J Med 353: 2590-2600
  17. Zecevic RD et al (2006) Lupus band test and disease activity in systemic lupus erythematosus: does it still matter? Clin Exper Dermatol 31: 358-360
  18. https://www.awmf.org/uploads/tx_szleitlinien/013-060l_S2k_Kutaner_Lupus_erythematodes_2020-06.pdf

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Please ask your physician for a reliable diagnosis. This website is only meant as a reference.

Authors

Last updated on: 26.08.2023