Tewfik KassaDermatologistMekelle University

CUTANEOUS LE (CLE)

• LE is a multisystem heterogeneous autoimmune connective-tissue disorder.

• Skin disease is the second most frequent clinical manifestation of LE

1 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

Prevalence of cutaneous manifestations in SLE over the Entire Course of Disease

Cutaneous80%• Photosensitivity 70%• Malar rash 50%• Oral ulcers 40%• Alopecia 40%• Discoid rash 20%• Vasculitis rash 20%• Other (e.g., urticaria, SCLE) 15%

• Interplay of genetic,Environmental (UV Viruses Drugs Chemicals)

hormonal factors.

-Loss of self- tolerance -Induction of Autoimmunity

CLE

• limited cutaneous involvement to devastating systemic disease.

-Nephritis-CNS dis.-Vasculitis

Cutaneous Lupus Erythematosus

• 3 categories of LE–specific skin diseases 1. acute cutaneous LE (ACLE), 2. subacute cutaneous LE (SCLE), and3. chronic cutaneous LE (CCLE). Clinical characteristics of each group are

unique

CLE

EPIDEMIOLOGY • ACLEAll races are affectedmuch more common in women than men (8:1). the malar rash in 20-60% of patients in LEAge– the malar rash is associated with a younger age of

disease onset

Epidemiology

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

years.

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.

Etiology

ETIOLOGY AND PATHOGENESIS• The cause(s) and pathogenetic mechanisms

are not fully understood. • Intertwined with SLE pathogenesis.

Lupus Erythematosus

• Auto-immune disease• Diverse clinical presentations• Production of autoantibody to components of

cell nucleus• Primary pathological processes– Complement activation– Inflammation– Vasculopathy

Immunological defects• T cell dysregulation• Polyclonal B cell activation• Defective immunoregulatory mechanisms– Autoantibody production– Clearance of immune complexes– Clearance apoptotic cells

Host factors

Role of Genetics• Genetic - concordance in twin studies– 25-50% monozygotic vs. 5% dizygotic

Role of Genetics…

• Linkage to >24 genes in human– Far more than other polygenic diseases– May explain diversity

• Estimated that at least 4 susceptibility genes needed to develop disease– MHC II (HLA DR2 & 3)– Complement C1q/C2/C4– TNFα, – T Cell receptor

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

Host factors

Sex Hormones• SLE → F:M ratio of 9:1• Effect of sex hormones on the immune system• High levels of estrogen and progesterone

promote humoral autoreactivity• Androgens shift the cytokine profile to that of

a Th1 CMI response

Environmental factors

• Ultraviolet radiation• Drugs• Viruses• Chemicals• Tobacco

Role of UV Light• The most important Environmental factor in the induction phase.

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.

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

Role of Drugs• inducing altered repair of DNA (T cell DNA hypomethylation)

• increased biological autoreactivity of lymphocytes.

• drugs reported to precipitate SCLE include– procainamide– Hydralazine

• Chemicals have been known to induce SLE–like illness. L-canavanine (alfalfa sprouts)Heavy metals

Role of Viruses • Infections of all types exacerbate SLE.• Rubella and CMV able to induce cell surface

expression of Ro/SS-A

• EBV can trigger SLE in susceptible individuals

• HIV

• In one study the onset of DLE lesions started with 1. Trauma → 11%, 2. Mental stress → 12%, 3. Sunburn → 5%, 4. Infection → 3%, 5. Exposure to cold → 2%6. Pregnancy → 1% 7. Spontaneously → In the

remainder (2/3).

Key Constituents in the Pathogenesis of Lupus

• DCs (present self-Ags to T-cells)

• IFN-αPlays a central role in the pathogenesis of SLE

• TLRs circulating DNA/anti-DNA complexes trigger TLR signaling

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

• ComplementGenetic deficiency of C1q, C4, and C2 is very

strongly ass. with the development of SLE

Pathogenesis…

• TNF-αInduces apoptosis (Fas/Fas-L)

• T cellsAutoreactive T cellsProvide help to autoreactive B cells

• B cellsThe production of autoantibodies by B cells

against nuclear antigens is the hallmark of SLE

Pathogenesis…• Four theoretical sequential phases:1. Inheritance of susceptibility genes, 2. Induction of autoimmunity, 3. Expansion of autoimmune processes, and 4. Immunologic injury.

Pathogenesis…

The first phase Susceptibility phase • Inheritance of genes that confer

predisposition to SLE.

The second phasethe induction phase • Initiation of autoimmunity – appearance of autoreactive T cells that exhibit

the loss of self-tolerance.

Pathogenesis…

The third phase Expansion phase • Perpetuation and expantion of aberrant clone.• Autoantibodies produced by clonally

expanded B cells.• Directed against nuclear antigens.

Pathogenesis…• Three major targets are the 1) Nucleosome (anti-DNA and antihistone antibodies), 2) Spliceosome (anti-Sm and anti-RNP antibodies) and

3) Ro and La molecules (anti-Ro and anti-LA)

The fourth stage immunologic injury heralds the onset of clinical disease action of autoantibodies and the immune

complexes they form

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

Presentation

CLINICAL MANIFESTATIONS• It is important to distinguish

among the subtypes of CLE–because the type of skin

involvement can reflect the underlying pattern of SLE activity.

Presentation…

• ACLE almost always occurs in the setting of acutely flaring SLE

• CCLE often occurs in the absence of SLE• SCLE occupies an intermediate position

Presentation…

Presentation…

• not uncommon to see more than one subtype of CLE in the same patient

ACLEButterfly malar rash

SymmetricErythematousEdematousMildly scaly

• Oral ulcerations

lesions on hands → Knuckles typically spared

• TEN-like lesions

Full-thickness epidermal necrosisDenudationBullae

SCLETypically photosensitive

Lesions confined to sun exposed skin

SCLE…Lesions may have – Annular variant– papulosquamous variant• Eczematous or psoriasiform

SCLE…• 10-15% develop SLE• Regular ass. with Anti-Ro autoantibody.strongly supports a diagnosis of SCLE

• EM-like lesions (Rowel syndrome)

CCLEDLE is the most common form of CCLE

Hyper- and hypopigmentation,Atrophic scarring,Follicular pluggingAdherent scales

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

• Mucosal DLE lesions

Erythematous chronic plaques

• Generalized DLE lesions occur both above and below the neck.

PainfulErosiveDisabling

• DLE characteristically affects the external ear

HyperpigmentedDilatedPlugged follicles

DLE…

Tendency for scarring

Prominent involvement of the adnexao Follicular pluggingo Scarring alopecia (Irreversible)

Dyspigmentation – Central hypopigmentation– Peripheral hyperpigmentation– Sts. Vitiligo-like depigmentation

~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;• anti–single-stranded DNA

antibody; • hypergammaglobulinemia; • an elevated ESR (especially

>50 mm/h); • Positive lupus band test;

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

Less common…Lupus TumidusIndurated erythematous lesionsNo scale or follicular plugging

Chilblain Lupus

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

Rare variants of CLEBullous LE– Distinct variant with autoantibodies to type VII collagen

Rare…Neonatal LE (NLE)o In children whose mothers have anti-Ro

autoantibodieso SCLE-like lesions

Non-specific cutaneous lesionso Vascular lesions are common– Periangual telngiectasia– Urticarial papules– Ulcerations– Atrophie blanche

– Purpura– Palmar erythema

–Raynaud’s phenomenon-The most common vascular reaction in lupus pts-Herald a worse prognosis

– Livedo reticularis

Rare…

o Non-scarring, reversible alopecia – ‘Lupus hairs’

CoarseDryBrittle

DDXDDX.• ACLESun burnRosaceaPhotodermatitisdermatomyositis

• Sun burn

Rosacea

DDX

• SCLEo Photosensitive eczemao Psoriasiso Dermatophytosiso Annular erythemas

DDX

• DLEPMLELymphoma cutisSarcoidosis LeishmaniasisCut. tbcGranuloma facialeLP

Diagnosis

Diagnosis…

HistopathologyTo establish the DxLess important for subtypingConsiderable overlap

Diagnosis…

• ACLENon-specificDamaged keratinocytesEdema in the upper dermis Lymphohistiocytic infiltrates in the upper dermis Vasodilatation with extrvasation of erythrocytes

Diagnosis…

• SCLEEpidermal atrophyDyskeratotic keratinocytes Lymphohistiocytic infiltrates in the upper dermis

Interface and perivascular pattern

Diagnosis…

• DLE Keratinocyte damage Colloid bodies Hyperkeratosis Melanin deposits within macrophages Thickened DEJ (PAS staining) Lymphohistiocytic infiltrates in the upper and lower dermis

– Interface, perivascular, and periadnexal locations

Folicullar plugging

Diagnosis…Lupus panniculitisPredominantly lobular Lymphohistiocytic

panniculitis

Lupus tumidusPronounced Lymphohistiocytic dermal

infiltrates (prominent in the lower dermis)Marked deposition of mucin

Immunofluorescence

• Deposition 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 components

• Examination of tissue may be performed on lesional or nonlesional skin.

• Nonlesional biopsies may be performed on sun-exposed or nonexposed surfaces.

Diagnosis…

• Testing 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)

Treatment

Topical therapyTopical or IL corticosteroids→ mainstay of therapy

High 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

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

Treatment…

• For antimalarial-resistant patients– Oral retinoids– Thalidomide – Gold– Clofazimine– Sulphasalazine– Immunosuppressive agents– Systemic corticosteroids– Dapsone

Adjunctive therapy• Sun avoidance• Sun protectionBroad-spectrum, high SPF sunscreensProtective clothing• Cosmetic cover-up• Discontinue smoking

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