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Tewfik Kassa Dermatologist Mekelle University

Cutaneous lupus erythematosus

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Text of Cutaneous lupus erythematosus

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Tewfik KassaDermatologistMekelle University

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CUTANEOUS LE (CLE)LE is a multisystem heterogeneous autoimmune connective-tissue disorder.

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Skin disease is the second most frequent clinical manifestation of LE1 malar rash2 discoid rash3 photosensitivity4 oral ulcers5 arthritis6 serositis7 renal disorder8 neurological disorder9 anaemia, leucopenia, lymphopenia, thrombocytopenia 10 ENA ds DNA, ENA Sm, antiphospholipid antibodies11 ANA

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Prevalence of cutaneous manifestations in SLE over the Entire Course of DiseaseCutaneous80%Photosensitivity70%Malar rash50%Oral ulcers40%Alopecia40%Discoid rash20%Vasculitis rash20%Other (e.g., urticaria, SCLE)15%

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Interplay of genetic,Environmental (UV Viruses Drugs Chemicals)hormonal factors.

-Loss of self- tolerance -Induction of Autoimmunity

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CLElimited cutaneous involvement to devastating systemic disease.

-Nephritis-CNS dis.-Vasculitis

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Cutaneous Lupus Erythematosus3 categories of LEspecific skin diseases acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE), andchronic cutaneous LE (CCLE). Clinical characteristics of each group are unique

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CLEEPIDEMIOLOGY ACLEAll races are affectedmuch more common in women than men (8:1). the malar rash in 20-60% of patients in LEAgethe malar rash is associated with a younger age of disease onset

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EpidemiologySCLE constitute 7 to 27% of LE patient populations. SCLE is more common in whites (85%).is primarily a disease of white femalesMale-to-female ratio of 1:4.SCLE typically occurs in patients aged 15-70 years.

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Epid.DLE is present in 15 to 30% of SLEmost common 20 and 40 years of age. can occur in infants and the elderlyF:M ratio of 3:2 to 3:1All races are affectedmight be more prevalent in blacks.

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Etiology ETIOLOGY AND PATHOGENESISThe cause(s) and pathogenetic mechanisms are not fully understood. Intertwined with SLE pathogenesis.

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Lupus ErythematosusAuto-immune diseaseDiverse clinical presentationsProduction of autoantibody to components of cell nucleusPrimary pathological processesComplement activationInflammationVasculopathy

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Immunological defectsT cell dysregulationPolyclonal B cell activationDefective immunoregulatory mechanismsAutoantibody productionClearance of immune complexesClearance apoptotic cells

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Host factorsRole of GeneticsGenetic - concordance in twin studies25-50% monozygotic vs. 5% dizygotic

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Role of Genetics

Linkage to >24 genes in humanFar more than other polygenic diseasesMay explain diversityEstimated that at least 4 susceptibility genes needed to develop diseaseMHC II (HLA DR2 & 3)Complement C1q/C2/C4TNF, T Cell receptor

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Role of Genetics

ACLE associated with HLA-DR2 and -DR3.SCLE HLA-DR3, DQA1*0501, DQB1*0502 haplotypeDLE significant increases of HLA-B7, -B8, -DR2, -DR3, and -DQA0102 a significant decrease in HLA-A2

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Host factorsSex HormonesSLE F:M ratio of 9:1Effect of sex hormones on the immune systemHigh levels of estrogen and progesterone promote humoral autoreactivityAndrogens shift the cytokine profile to that of a Th1 CMI response

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Environmental factorsUltraviolet radiationDrugsVirusesChemicalsTobacco

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Role of UV LightThe most important Environmental factor in the induction phase.

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Role of UV Light

UV light induce keratinocyte apoptosis displace autoantigens such as Ro/SS-A and La/SS-B from inside epidermal keratinocytes to the cell surface. cell surface autoantigen expression.

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Role of Tobacco Exposuresmokers are at a greater risk of developing SLE than are nonsmokers (Lipogenic aromatic amines)an increased frequency of DLE in smokers

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Role of Drugsinducing altered repair of DNA (T cell DNA hypomethylation)increased biological autoreactivity of lymphocytes. drugs reported to precipitate SCLE includeprocainamideHydralazine

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Chemicals have been known to induce SLElike illness. L-canavanine (alfalfa sprouts)Heavy metals

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Role of Viruses Infections of all types exacerbate SLE.Rubella and CMV able to induce cell surface expression of Ro/SS-AEBV can trigger SLE in susceptible individualsHIV

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In one study the onset of DLE lesions started with Trauma 11%, Mental stress 12%, Sunburn 5%, Infection 3%, Exposure to cold 2%Pregnancy 1% Spontaneously In the remainder (2/3).

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Key Constituents in the Pathogenesis of LupusDCs (present self-Ags to T-cells)IFN-Plays a central role in the pathogenesis of SLETLRscirculating DNA/anti-DNA complexes trigger TLR signaling

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ApoptosisIncreased apoptosis of peripheral blood mononuclear cells (SLE)Keratinocytes (CLE)

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ComplementGenetic deficiency of C1q, C4, and C2 is very strongly ass. with the development of SLE

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PathogenesisTNF-Induces apoptosis (Fas/Fas-L)T cellsAutoreactive T cellsProvide help to autoreactive B cells

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B cellsThe production of autoantibodies by B cells against nuclear antigens is the hallmark of SLE

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PathogenesisFour theoretical sequential phases:Inheritance of susceptibility genes, Induction of autoimmunity, Expansion of autoimmune processes, and Immunologic injury.

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PathogenesisThe first phase Susceptibility phase Inheritance of genes that confer predisposition to SLE.

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The second phasethe induction phase Initiation of autoimmunity appearance of autoreactive T cells that exhibit the loss of self-tolerance.

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PathogenesisThe third phase Expansion phase Perpetuation and expantion of aberrant clone.Autoantibodies produced by clonally expanded B cells.Directed against nuclear antigens.

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PathogenesisThree major targets are the Nucleosome (anti-DNA and antihistone antibodies), Spliceosome (anti-Sm and anti-RNP antibodies) and Ro and La molecules (anti-Ro and anti-LA)

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The fourth stage immunologic injuryheralds the onset of clinical diseaseaction of autoantibodies and the immune complexes they form

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cause tissue damage by means ofdirect cell death, cellular activation, opsonization, and the blocking of target molecule function.

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Presentation CLINICAL MANIFESTATIONSIt is important to distinguish among the subtypes of CLEbecause the type of skin involvement can reflect the underlying pattern of SLE activity.

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PresentationACLE almost always occurs in the setting of acutely flaring SLECCLE often occurs in the absence of SLESCLE occupies an intermediate position

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Presentation

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Presentationnot uncommon to see more than one subtype of CLE in the same patient

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ACLEButterfly malar rash

SymmetricErythematousEdematousMildly scaly

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Oral ulcerations

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lesions on hands Knuckles typically spared

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TEN-like lesions

Full-thickness epidermal necrosisDenudationBullae

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SCLETypically photosensitiveLesions confined to sun exposed skin

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SCLELesions may have Annular variantpapulosquamous variantEczematous or psoriasiform

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SCLE10-15% develop SLERegular ass. with Anti-Ro autoantibody.strongly supports a diagnosis of SCLE

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EM-like lesions (Rowel syndrome)

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CCLEDLE is the most common form of CCLE

Hyper- and hypopigmentation,Atrophic scarring,Follicular pluggingAdherent scales

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sharply demarcated, coin-shaped (i.e., discoid) erythematous plaques covered by a prominent, adherent scale.

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Mucosal DLE lesions

Erythematous chronic plaques

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Generalized DLE lesions occur both above and below the neck.

PainfulErosiveDisabling

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DLE characteristically affects the external ear

HyperpigmentedDilatedPlugged follicles

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DLETendency for scarring

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Prominent involvement of the adnexaFollicular pluggingScarring alopecia (Irreversible)

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Dyspigmentation Central hypopigmentationPeripheral hyperpigmentationSts. Vitiligo-like depigmentation

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~5% DLE SLERisk factors for the development of SLE:

diffuse nonscarring alopecia; generalized lymphadenopathy;periungual nail fold telangiectasia; Raynaud's phenomenon; SCLE/ACLE skin lesions; vasculitis; unexplained anemia;

Marked leukopenia; false-positive tests for syphilis; persistently positive high-titer ANA assay;antisingle-stranded DNA antibody; hypergammaglobulinemia; an elevated ESR (especially >50 mm/h); Positive lupus band test;

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LESS COMMON SUBTYPESLupus Panniculitis/ProfundusIndurated plaquesCan evolve into disfiguring, depressed areas

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Less commonLupus TumidusIndurated erythematous lesionsNo scale or follicular plugging

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Chilblain Lupus

Red or dusky purple plaques on the fingers, toes.After cold exposure

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Rare variants of CLEBullous LEDistinct variant with autoantibodies to type VII collagen

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RareNeonatal LE (NLE)In children whose mothers have anti-Ro autoantibodiesSCLE-like lesions

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Non-specific cutaneous lesionsVascular lesions are commonPeriangual telngiectasiaUrticarial papulesUlcerationsAtrophie blanche

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PurpuraPalmar erythema

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Raynauds phenomenon-The most common vascular reaction in lupus pts-Herald a worse prognosisLivedo reticularis

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RareNon-scarring, reversible alopecia Lupus hairs

CoarseDryBrittle

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DDXDDX.ACLESun burnRosaceaPhotodermatitisdermatomyositis

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Sun burn

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Rosacea

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DDXSCLEPhotosensitive eczemaPsoriasisDermatophytosisAnnular erythemas

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DDXDLEPMLELymphoma cutisSarcoidosis LeishmaniasisCut. tbcGranuloma facialeLP

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Diagnosis

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DiagnosisHistopathologyTo establish the DxLess important for subtypingConsiderable overlap

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DiagnosisACLENon-specificDamaged keratinocytesEdema in the upper dermisLymphohistiocytic infiltrates in the upper dermis Vasodilatation with extrvasation of erythrocytes

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DiagnosisSCLEEpidermal atrophyDyskeratotic keratinocytesLymphohistiocytic infiltrates in the upper dermisInterface and perivascular pattern

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DiagnosisDLEKeratinocyte damageColloid bodiesHyperkeratosisMelanin deposits within macrophagesThickened DEJ (PAS staining)Lymphohistiocytic infiltrates in the upper and lower dermisInterface, perivascular, and periadnexal locationsFolicullar plugging

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DiagnosisLupus panniculitisPredominantly lobular Lymphohistiocytic panniculitis

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Lupus tumidusPronounced Lymphohistiocytic dermal infiltrates (prominent in the lower dermis)Marked deposition of mucin

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ImmunofluorescenceDeposition of Ig and/or complement at the DEJ is a characteristic feature of LE. All 3 immunoglobulin classes IgG, IgM, IgA and a variety of complement componentsExamination of tissue may be performed on lesional or nonlesional skin. Nonlesional biopsies may be performed on sun-exposed or nonexposed surfaces.

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DiagnosisTesting of nonlesional nonexposed skin is termed the lupus band test (LBT).Nonlesional positive LBT correlate strongly with an aggressive course of systemic disease (LE-Nephritis)

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Treatment

Topical therapyTopical or IL corticosteroids mainstay of therapyHigh potency steroids (for DLE lesions even on the face)Systemic therapyAntimalarials (the gold standard systemic therapy)Hydroxychloroquine (the most commonly chosen)200mg qd/bidThe response is slow 2 to 3 months

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patients with LE skin disease who smoke are less responsive to antimalarial treatment.

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TreatmentFor antimalarial-resistant patientsOral retinoidsThalidomide GoldClofazimineSulphasalazineImmunosuppressive agentsSystemic corticosteroidsDapsone

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Adjunctive therapySun avoidanceSun protectionBroad-spectrum, high SPF sunscreensProtective clothingCosmetic cover-upDiscontinue smoking

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