Lupus erythematosus systemic M32.9

Author: Prof. Dr. med. Peter Altmeyer

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

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Last updated on: 29.10.2020

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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 progression.

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

In the past, clinical diagnosis was carried out according to the criteria of the ARA (American Rheumatism Association), but these criteria do not adequately reflect the real clinical conditions and should be revised. In 2012 a new classification was therefore 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. localised or generalised discoid lupus erythematosus)
  • Oral ulcers (palate or nose)
  • Non-scarring alopecia (or diffuse effluvium)
  • Synovitis or pressure pain (2 or >2 joints) and morning stiffness (30 min or longer)
  • Serositis (pleurisy or pericardial pain lasting more than 1 day)
  • Kidney involvement (single urine: protein/creatinine ratio or protein in 24h-collection urine, disk electrophoresis: proteinuria: >500mg/d or cylindruria)
  • Neurological involvement (e.g. epilepsy, psychosis, myelitis)
  • Hemolytic anemia
  • Leukopenia (<4,000ul) or lymphopenia (<1,000ul)
  • Thrombocytopenia (< 100,000/ul)

Immunological criteria:

  • Chromatin Ac
  • ANA titre above the laboratory reference value
  • Anti-dsDNA antibodies = Anti-nDNA-Ak - ds=double stranded - n=native
  • Anti-ssDNA-Ak ss= single stranded
  • Anti-Histon-Ak
  • Anti-Sm antibodies
  • Anti-phospholipid antibodies (anti-cardiolipin and anti beta2 glycoprotein antibodies, false positive VDRL)
  • Reduced 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%

Occurrence/Epidemiology
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Prevalence: 36/100.000; incidence: 5-10/100.000. In childhood, the prevalence should be reduced by a power of ten. Depending on the ethnicity, different frequencies can be observed, e.g. systemic LE is 4 times more common among Africans than among Caucasians or Asians.

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

These autoantibodies, which are typically directed against nucleic acids in SLE, form immune complexes with "self" nucleic acids from cell debris. The deposition of these immune complexes in the vessels initiates inflammatory processes on the one hand. On the other hand, uptake of the immune complexes by plasmacytoid dendritic cells via TLR signalling cascades stimulates further IFN-α production. In this way, a vicious circle is formed, which leads to the breakdown of immunological tolerance and thus to autoimmunity. Consequently, the organism must have suitable mechanisms at its disposal which on the one hand guarantee a prompt and efficient immune response to viral nucleic acids, but on the other hand protect against an inadequate activation of the immune system by the body's own nucleic acids.

A mutation in the TREX1 gene, a gene encoding an intracellular DNase (see nucleases below), which plays an important role in apoptosis, was detected in a smaller proportion of patients. There is evidence that an increased tendency to apoptosis and a decreased clearance of apoptotic material is an important pathogenetic principle of SLE.

Triggering factors:

UV irradiation(inducing apoptosis)

Drugs (antihypertensives, procainamide, anticonvulsants, INH, antibiotics, antifungals e.g. terbinafine, oral anticonceptives, thiazide diuretics, NSAIDs, atorvastatin)

trauma, psychological stress, pregnancy

basic visceral diseases (tuberculosis, hepatitis, kidney diseases).

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), regardless of their origin.

Regulatory T cells (Treg) also play an important role in the prevention of autoimmune diseases in a healthy organism.

Manifestation
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  • Occurs mainly in younger adults.
  • Ratio of women to men (w:m) is 4:1.
  • The so-called "late onset SLE" occurs after the 50th year (w:m=2:1).
  • The so-called juvenile onset SLE occurs on average at the age of 12 years (w>m; incidence 0.9/100,000 per year); preferred in African Americans; less frequently in Caucasians.

Clinical features
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  • General symptoms are evident in 95% of SLE patients: fever, weakness, weight loss, arthralgia.
  • Other organ changes: polyarthritis, 50-65% of SLE patients have kidney involvement (lupus nephritis, nephrotic syndrome), lymph node swelling, wet pleuritis (40-60%), more rarely 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%) such as headache, cognitive impairment, psychosis and depression but also cerebro-organic symptoms such as seizures and transverse myelitis.
  • Skin lesions are present in about 75% of patients. In about 25% of patients they are the first symptoms of the disease.
  • The skin lesions can be divided into frequent and less frequent, specific and non-specific (lupus-associated) skin lesions:
    • Commonly available specific HV:
      • "Butterfly erythema": Persistent, blurred, butterfly-like erythema of the face.
      • Morbilliform, scarlatiniform, multiform, large-area (rosacea or livedo) or bullous exanthema (especially upper back and chest areas)
      • Localized, pityriasiform, firmly adherent scaling or spatter-like atrophy.
      • With increasing duration of the erythema, flat livid-red plaques develop (especially in the late-onset type), preferably in the front breast area as well as on the shoulders, hands and fingers. The plaques develop flat (sometimes painful) keratoses, splatter-like whitish atrophy, telangiectasia, erosions with crusts. Overall, a poikilodermatic clinical picture may develop (see figure).
      • Localized, spotty or diffuse erythema and plaques, especially on the end of fingers and toes.
    • Less frequently existing specific HV:
    • Associated (non-specific) HV:
  • Mucous membrane changes: Edematous, livid enanthema of the oral mucosa with extensive erosions and ulcerations especially on the hard palate and the cheek mucosa. Exudative, encrusted cheilitis with a tendency to atrophy.
  • Drug-induced lupus, less severe lupus erythematosus, is generally limited to the following symptoms: polyarthritis, pleuritis/pericarditis; no CNS or kidney involvement, furthermore ANA+, often anti-histon-Ak, usually no anti-DNA-Ak!
  • In order to measure activity and damage of mucocutaneous Mainfestations, the CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) was developed and validated.

Laboratory
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  • Non-specific activity symptoms:
    • BSG increase (often correlated with the severity of the disease phase), CRP increased.
    • Often antibody induced cytopenia: leukopenia, neutropenia, left shift, lymphopenia, eosinopenia, thrombopenia, macrocytic anaemia.
    • Reticulocytes and LDH increased
    • Signs of complement activation (lowering of C3 and C4 or CH50).
    • Electrophoresis: hypalbuminemia, hypergammaglobulinemia.
    • Cryoglobulins, circulating immune complexes possible
    • In 33% of cases false positive rheumatoid factor, but also false negative rheumatoid factor is possible, Coombs test heaped positive.
    • In 25% of cases false positive syphilisserology (VDRL).
  • Specific activity phenomena:
    • ANA: positive to 95% (high titer) - titer does not correlate with the disease activity!
    • Anti-dsDNA-Ak: positive to 70%. Titres correlate with activity (Note: in most cases the decrease of the complement factors is parallel to the increase of the titre!)
    • Anti-Sm -Ak: positive to 30%.
    • Anti-Ro-Ak (SSA): positive at 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 antibody
    • Phospholipid antibodies (positive 35%)
    • Urine: depending on kidney involvement proteinuria, haematuria and cylindruria.

Antinuclear antibodies (homogeneous, speckled, peripheral or nucleolar pattern), antibodies against defined 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, thrombocytes). 30-50% of patients have antiphospholipid Ac. 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 often shows H1 and H3 histone antibodies. Histone AK 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 a few randomized controlled trials. Personal expertise of many years is therefore an important prerequisite for an 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. kidney involvement) require specialist treatment.
    • Antimalarials: In patients without organ-threatening manifestations (skin-joint pleuritis), monotherapy with antimalarials should be sufficient in the long term. Initially these are combined with non-steroidal anti-inflammatory drugs and/or glucocorticoids (see below). The glucocorticoid dose should be reduced to 5.0-7.5 mg (prednisolone equivalent) under this therapy regime. If this is not possible, the use of immunosuppressive drugs is indicated.
      • Chloroquine (e.g. Resochin) or alternatively hydroxychloroquine (e.g. Quensyl) have a firm place in basic therapy for mild forms of SLE with predominant joint and skin involvement in combination with a low prednisolone dose(long-term therapy up to max. 7.5 mg/day p.o.). Initial therapy with chloroquine 6.0-6.5mg/kgkgKG p.o., after 2 weeks reduction to 250 mg/day. Hydroxychloroquine is administered with a dosage of 3.5-4.0 mg/kgKG /day p.o. over 4 weeks.
    • Glucocorticoids: Prednisolone (e.g. Decortin H) is generally accepted as standard therapy in the basic medication of choice. The amount of the initial dose depends on the disease activity.
    • Slight manifestation of the disease (skin, musculoskeletal system, Raynaud's disease): Peroral application of 0.25-0.5 mg/kg bw as a morning single dose.
    • Moderately severe disease manifestation (skin, musculo-skeletal system, leukopenia, discrete kidney involvement, mild pleuropericarditis): 0.5-1.0 mg/kg bw, divided into 2-3 doses (e.g. 50-25-0 or 50-25-25 mg p.o.).
    • Severe disease manifestation (severe lupus nephritis, CNS involvement, pleuropericarditis, necrotising 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 single dose. In case of dose reduction reduce evening and midday dose rather than the morning dose. From a total dose of 25 mg/day onwards, further reduction in the form of the "alternate day" mode, e.g. 25 and 20 mg or 25 and 15 mg alternating daily. As a maintenance dose, 10 and 5 mg should be aimed for.
    • Azathioprine (e.g. Imurek): is generally accepted as the standard therapeutic agent for moderate and severe forms (in case of insufficient response to a combination therapy with antimalaria/prednisolone - prednisolone dose cannot be reduced below 10 mg). Initial dose of 2-3 mg/kg bw p.o. Dose is distributed over 2-3 ED. Effect starts 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 manifestation. No effect in severe kidney or CNS infection. 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. folican) is 2 days later than methotrexate.
    • Alternatively: Mycofenolate mofetil 1.0 g/2 times/day p.o. in combination with prednisolone p.o. (For dosages see above)
    • Alternative: Cyclophosphamide (e.g. Endoxan): 1-2 mg/kg bw/day p.o. or 1000 mg i.v. every 4 weeks. Effect starts after about 1 week. High teratogenic effect. Use only in severe and life-threatening cases. Only for severe lupus nephritis together with prednisolone therapy of the 1st choice. Weekly blood count controls. Duration of oral therapy 4-6 weeks, then 1 week therapy break, followed by a 3-week therapy break, followed by a 1-week therapy break. Max. Therapy duration 6-10 months.
    • Alternative: Ciclosporin A (e.g. sand immune): Seems to have a beneficial effect on SLE. The recommended dose is 3-5 mg/kg bw/day divided over 2 days of treatment. The optimal blood level is 100-200 mg/ml blood (determination in specialized laboratories possible). Its use is limited by nephrotoxicity and hepatotoxicity as well as hypertension.
    • Alternative: plasmapheresis (or immunoadsorption): therapeutic approach to eliminate circulating immune complexes and autoantibodies. Currently still controversial discussions, favourable 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), if a pronounced leukopenia (especially granulocytopenia with frequent infections) or thrombopenia does not allow the use of antimetabolites or alkylancients.
    • Alternative: Belimumab (Benlysta): Human monoclonal IgG1λ antibody which 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.
    • Supplementary: 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): On the basis of individual case reports it is very effective in patients with lupus arthritis ( off-label use). 100 mg s.c. once/day in combination with methotrexate. Alternatively Anakinra can be combined with Leflunomide (Arava).
    • A smaller study exists on tocilizumab. A significant improvement in the disease activity of SLE was found in 8 out of 15 patients. Arthritis improved in 7 patients, and the concentration of DNA-AK was reduced, as were 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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  1. Albrecht J et al (2004) Dermatology position paper on the revision of the 1982 ACR criteria for systemic lupus erythematosus. Lupus 13: 839-849
  2. Brinster NK (2012) Nonbullous neutrophilic lupus erythematosus: A newly recognized variant of cutaneous lupus erythematosus. J Am Acad Dermatol 66: 92-97
  3. Da Cruz Silva LL (2015) Persistent eyelid edema and erythema as manifestations of lupus erythemtodes: a series of 6 cases. JDDG 13: 917-920
  4. Enk AH, Knop J et al (2000) Successful management of systemic lupus erythematosus with IgM enriched immunoglobulins. dermatologist 51: 416-418
  5. Garsenstein M et al (1962) Systemic lupus erythematosus and pregnancy. New Engl J Med 267: 165-168
  6. Fu SM et al (2003) Autoantibodies and glomerulonephritis in systemic lupus erythematosus. Lupus 12: 175-180
  7. Hashemi H et al (2015) Juvenile systemic lupus erythematosus with the unusual manifestation of lupus-associated panniculitis. Dermatologist 66: 719-720
  8. Kolb-Maurer A et al (2002) Vesicle, light hypersensitivity, mouth ulceration and arthralgia in a 40-year-old patient. Bullous systemic lupus erythematosus. Dermatologist 53: 202-206
  9. Kuhn A et al. (2015) Diagnosis and therapy of systemic lupus erythematosus, Dtsch Ärztebl Int 112: 423-434
  10. Mok CC et al (2003) Pathogenesis of systemic lupus erythematosus. J Clin Pathol 56: 481-490
  11. Petri M et al (2012) Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus.arthritis rheumatism 64: 2677-2686
  12. Pfeiffer C (2011). Systemic lupus erythematosus with cutaneous involvement in a patient with heterozygous TREX1 mutation. Abstract Volume 46 Conference DDG P10/07
  13. Rothenberg RJ et al (1988) The use of methotrexate in steroid-resistant systemic lupus erythematosus. Arthritis Rheum 31: 612-615
  14. Wagner J et al (1991) Contraceptives and systemic lupus erythematosus. Dermatologist 42: 726
  15. Williams WW et al (2005) A 29-year-old pregnant woman with nephrotic syndrome and hypertension. N Engl J Med 353: 2590-2600
  16. 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

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

Authors

Last updated on: 29.10.2020