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The Clinical spectrum of Lupus
erythematosus is defined by cutaneous LE
limited to the skin at the one extreme and
by multisystem disease with diffuse
proliferative glomerulonephritis at the
other.
Cazenave introduced the name LE in 1851.
Kaposi was first to recognise the systemic
components of LE
Epidemioloigy
-Skin disease is the
second most frequent clinical
manifestation of LE after joint
inflammation.
-All races are affected
-ACLE like SLE is more common in women
than men(8:1)
-SLE is 7fold more common than DLE.
SCLE is primarily a disease of white females,
with the mean age of onset in the fifth decade.
DLE can occur in infants and the elderly, it is
most common in individuals between 20 and 40
years of age.
DLE has a female:male ratio of 3:2 to 3:1, more
prevalent in blacks.
90% of SLE patients are women of Child bearing
age group, highest prevalence is seen in African
and Americans.
Revised ARA Criteria
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Malar Rash
Discoid Rash
Photo sensitivity
Oral ulcer
Arthritis
Serositis
Renal disorder
Neurologic disorder
Hematologic disorder
Immunologic disorder
Anti Nuclear antibodies
Etiopathogenesis
4 theoretical phases
1. Susceptibility phase:
involves the inheritance of gene that confer
predisposition to injury. HLA class II antigen
are more clossely assosiated with
sp.autoantibody. Genes for complement
proteins & TNF, genes mediating apoptosis,
Gene involved in T-cell signalling process and
genes for Clearance of immune complex are
implicated.
2. Induction phase:
involves the initiation of autoimmunity
characterised by the appearance of
auto reactive T-Cell that exhibit the loss
of self tolerance. Envrionmental factors
play an important role.
3. Expansion stage:
involves progressive augmentation of
the autoimmune response and has
feature of an antigen driven response.
Serological detectable auto antibodies
are produced by the population of
clonally expanded B-cell.
Three major target of antibodies:
a. Nucleosome- anti DNA & anti histone
antibody
b. Splicesome – anti Sm & anti RNP As
c. Ro & La molecules – Anti Ro & La.
4. Immunological injury:
This phase can be attributed to the action
of auto antibodies and the immune
complex that form, which causes tissue
damage by direct cell death, cellular
activation, opsonization and blocking of
the target molecule functions.
Role of genetics in LE specific skin
disease:
SLE- HLA DR2, DR-3, B8
SCLE – HLA B8, DR-3 (annular), DR-2 (papulo
squamous)
Genetic deficiency of complement components
including C2-5 & C1 esterase inhibitor
deficiency SCLE & DLE
DLE- HLA B7, B8, DR2, DR3 & DQA 0102.
Cutaneous LE IL1 receptor antagonist & TNFα
gene polymorphism
Role of UV light in LE specific skin disease:
UV Light: Most important environmental factor in
the induction phase.
Uncover an already established auto immune state
by triggering auto Ag release from injured
keratinocytes.
Have early critical role in the induction phase by
altering cellular DNA.
Affect localization of preexisting autoantibody
containing immune complex by altering
endothelial permeability
UV induced keratinocyte apoptosis-responsible for
aberrant pattern of cell surface auto Ag
expression.
Exaggerated release of immune mediators like IL1,
TNFα PG-E, protease, O2 free radicals &
histamines
Role of Tobacco exposure:
Smoking- ↑ risk of developing SLE.
Related to lupogenic aromatic amines contained
in tobacco smoke.
Other Factors:
Heavy metals, dietary supplements of
alfalfa,silica,infection,stress,hormonal factors
Late menarche is associated with increased risk
of SLE
Infection of all types of viruses are known to
exacerbate SLE.
Role of Drugs:
Allopurinol, Atenolol, Captopril,
carbamazepine, chlorpromazine, gold,
hydralazine, hydrochlorothiazide, INH,
Lithium, methyldopa, minocycline,
nitrofurantoin, OCP, penicillamine, Phenyl
butazone, phenytoin, phenothiazine,
procainamide, propranalol, sulfonamides,
tetracycline & Valproate.
Drug induced LE: 82% have anti
histone Ab
↑ incidence in HLA DR-4, more common
in females(4:1).
> in slow acetylators.
Similar manifestation to SLE, without
cutaneous involvement
Hydralazine: inhibits binding of C4
Drug induced SCLE-skin is often involved
DRUGS Hydrochlorothiazide, CCB, ACE,
Terbinafine, piroxicam, d-penicillamine,
sulfonylureas, oxprenalol, parental gold,
Spironolactone, IFNβ & Ranitidine.
LE specific skin lesions
Chronic Cutaneous LE(CCLE):
1.DLE.
Skin lesions:
discrete erythematous plaques, well defined adherent
scale that extend to dilated hair follicles. Heal with
atrophy, telangiectasia in the centre.
Scalp involvement- alopecia (follicular
distruction)
Mucous membrane involvement in 15%.
Disseminated DLE: lesions occur both above
and below neck.
1.3- 6.5% localised & 22% disseminated DLE
cases develop SLE.
1/4th patients with SLE develop DLE lesions in
some point in the course of their illness
Clinical features that suggest SLE in
patients with DLE skin lesions:
History: Unexplained fever, Extreme fatigue,
joint pain, raynauds phenomenon, pleuritic
chest pain, photosensitivity, LE non specific
but disease related skin lesions.
Physical findings: Diffuse hair loss,
lymphadenopathy, SCLE/ACLE skin lesions.
Lab anomalies: unexplained anemia,
Leucopenia, ↑ESR, positive ANA, hyper
gamma globulinemia, Immune deposit at DEJ
of clinically normal skin.
Histopathology:
Basal/germinal cells of epidermis is the principal
site in injury.
Prominent hyperkeratosis, well developed
follicular plugging, nucleated layer of epidermis
may be thinned out.
Loss of normal organization of basal cells;
Edema with vacuole formation within basal cells.
Partial obliteration of DEJ by a mononuclear
cell infiltrate.
Accumulation of melanin in dermal
macrophages.
Liquifactive degeneratin of the basal cell layer.
Mononuclear infiltrate in dermis composed
predominant of T-lymphocyte, localized to
periappendegeal and perivascular areas.
Immunopathology of DLE
Thick band of Ig along DEJ in lesional skin.
Deposits are heavy and contain several Ig
classes.
Homogeneous, thready or granular pattern
Do not occur in uninvolved skin.
In scarring alopecia, deposits occur around
hair follicles.
Differential Diagnosis:
Plaque type of PLE, Granuloma Facie,
Sarcoidosis, Jesners lymphocytic
infiltrate, pseudolymphoma,
lymphocytoma cutis, lupus vulgaris,
tertiary syphilis
Hypertrophic LE:
Keratoacanthoma, SCC, Prurigo
nodularis, hypertrophic LP.
Laboratory Findings
Low titre ANA in 30%.
5% will have positive ANA at significant
titre.
Small percentage will have false +VDRL,
RA factor, slight decrease in serum
complement, moderate increase in Ig,
modest leucopenia, and even
antiphospholid Ab.
CCLE- OTHER FORMS
LE panniculitis/Lupus profundus
Deep dermal and subcutaneous inflammatory
involvement.
Deep, firm, nodules often without surface
changes.
Histopathology: Insignificant epidermal
involvement, perivascular lymphocytic
involvement in deep dermis and SC fat, vessel
wall thickening, prominent fibrinoid
degeneration of collagen and calcification..
2.Hypertrophic or Verrucous DLE:
Extensor aspect of arm, upperback and face.
Overlapping features of hypertrophic LP and
LE have been described.
3. MUCOSAL LE:
Oral, nasal, conjunctival and genital.
Oral mucosal LE can degenerate to SCC
similar to long standing cutaneous DLE
lesions.
4.Chilblain/perniotic LE:
Precipitated by cold, damp climate.
Associated with Ro, SSA Ab.
20%SLE.
5.Tumid LE:
Succulent, edematous urticaria appear in
plaques with little surface changes.
On histology, typical dermal findings of DLE
are seen and characteristics epidermal
histological changes of LE specific skin
disease are minimally expressed.
Nail changes: Red blue colour of the nail
plate, longtitudional striae,crumbling of
nails, subungual hyperkeratosis.
Rowell syndrome: Cutaneous LE occur with
lesions resembling EMF on face, neck,
chest and mouth.
Subacute Cutaneous LE
Antibodies to the Ro, SSA antigens are closely
associated.
Comprise approximately 10% of patients with LE.
2 types: papulosquamous(2/3), annular polycyclic(1/3)
Predominantly adults.
Usually occur above the waist, around the neck, on
the trunk, and on outer aspect of the arm.
50% fulfill ARA criteria for SLE.
Fever, Malaise and CNS involvement occur, but renal
disease is mild and infrequent.
SCLE VS DLE
SCLE: less scarring less prominent
scaling and follicular plugging, less
persistent, more wide spreading
distribution, less discrete.
More promninent pigmentary changes,
but not associated with dermal atrophy.
Photosensitivity is very common.
LE lesions of hard palate in 40%.
Diffuse, nonscarring alopecia.
Livedo reticularis and periungual
telangiectasia more in SCLE.
Almost all patients have mild systemic
complaints: joint pain, unexplained
fever, malaise.
20% will have DLE/ACLE lesions.
Pathology
Similar to DLE,
however follicular plugging, hyperkeratosis, and
density and depth of cellular infiltrate are
considerably less.
The mononuclear cell infiltrate is usually
restricted to the perivascualr and
periappendigeal areas of upper third of dermis.
The diagnostic findings are found along the
basal layer of the epidermis, as seen in all
forms of LE specific skin disease.
Pilosebaceous atrophy is the only significant
preidctor of DLE vs SLE.
Immunopathology
In contrast to the frequent finding of Ig
deposits of DLE, 40-50% of SCLE lesions
do not have immune deposits at DEJ.
IgG is deposited in a dust like pattern
over the nucleus and cytoplasm of
epidermal keratinocyte and cells in
upper dermis.
D/D:
Papulosquamous SCLE: Photo sensitive
variant of psoriasis.
Annular SCLE: EMF, EAC, EGR, GA.
Seborrhoeic dermatitis, PMLE, Dermatophyte
infection, Nummular Eczema, CD,
Dermatomyositis, PRP, Disseminated
superficial actinic porokeratosis, Cutaneous
lymphoma/Mycosis fungoidis.
Acute Cutaneous LE(ACLE)
Localized ACLE: Classic butterfly rash or
malar rash of SLE.
Confluent symmetric erythema and
edema is centred over the malar
eminence and bridge of the nose,
Characteristically sparing the nasolabial
fold.
Forehead, chin and V area of the neck can
be involved and severe facial swelling can
occur.
Generalized ACLE:
Wide spread morbilliform or exanthematous
eruptions often focussed on extensor aspect
of arms and hands characteristically sparing
the knuckles.
An extremely acute form of ACLE, simulating
TEN can occur.
ACLE lesions are abrupt in onset, last for hours
to days, and frequently coincide with systemic
disease exacerbation.
Post inflammatory hyper pigmentation is
common, no scarring.
ACLE occasionally occur in conjunction to
SCLE, but unusual with DLE.
Histopathologically:
Early phase unimpressive and non diagnostic.
Careful examination will revive the basal layer
changes characteristic of cutaneous LE.
Dermal cellular infiltratives is usually sparse
and the most prominent change being upper
dermal edema and focal areas of basal area
injury.
Upper dermis: pronounced mucinosis.
Epidermal necrosis can occur.
DIF:
Immune deposits at DEJ in skin lesions(90%)
and uninvolved skin(60%)
D/D:
Localized ACLE-Rosacea, Dermatomyositis,
Seborrhoeic dermatitis, PMLE, Photo allergic
CD.
Generalized ACLE-Drug hypersensitivity,Viral
exanthem.
LE Nonspecific skin lesions:
Their presence indicates skin disease.
Vascular lesions- most common; telengiectasia(Linear
nail fold capillary dilatation)
Deepset papular, palmar and distal telengiectasic
lesions are characteristic of LE
Dermal vasculitis with ischaemic infarcts.
Recurrent superficial and deep thrombophlebitis may
be an early sign.
20% can have raynauds phenomenon( associated with
good prognosis).
5% will have rheumatoid nodules.
A deforming non erosive
arthritis(Jaccoud’s arthritis may be seen
in these patients. They have high
frequency of endocarditis.
Hair loss:CCLE-scarring alopecia.
SLE-frontal alopecia with increased
fragility producing short, broken of
hairs(lupus hairs)
Mucous membrane lesions usually
occurs during acute flares.
Diffuse cutaneous hyper pigmentation
may be seen.
Urticarial like eruptions may be seen.
Others: EMF, papulonodular mucinosis,
PCT.
A. Bullous Lesions in LE:
1. ACLETEN like ACLE
2. SCLE:
TEN like SCLE
Vesiculo bullous annular SCLE
3. CCLE:
Bullous DLE
B. LE Non specific vesiculobullous LE:
1. Bullous SLE
2. Vesiculo bullous disorder anecdotaly
occur in LE
BP, DH, PE, PCT
Extra cutaneous manifestations of SLE
1. General:
Fever, fatigue, malaise, weight loss.
2. Musculoskeletal:
Symmetric small joint arthralgia, morning
stiffness, myalgia, myositis, periarticular
calcification, tendinitis, avascular bone
necrosis.
Salmonella infectionseptic arthritis.
Lupus Foot: abnormalities of feet with clawing of
toes and flexion contractures.
3. Hematological:
Anemia-normocytic
normochromic/hemolytic.
Leucopenia-lymphopenia, granulocytopenia,
thrombocytopeina.
4. Cardiopulmonary:
Pleurisy, pleural effusion, aseptic pneumonitis,
pulmonary hemorrhage, pericarditis, cardiomegaly,
CCF, conduction defects, coronary arteritis,
Libmansack endocarditis,
Diaphragmatic fibrosis shrinking lung syndrome.
\
5. Renal:
Mesangioglomerulonephritis(Class2)
-mild proteinuria.
Focal proliferative GN(Class3)
-proteinuria, hematuria, occasionally nephrotic
syndrome.
Diffuse proliferative GN(Class4)
-proteinuria, hematuria, redcell cast, nephrotic
syndrome, HTN.
Membranous GM(Class 5)
Severe proteinuria, nephrotic syndrome.
End stage scarred glomeruli(class 6)
6. Neuropsychiatric:
Peripheral neuropathy, transverse myelitis, GBS,
chorea, athetosis, seizures, headache, multiple
sclerosis.
Brain infarcts secondary to cerebral arteritis.
Psychological- depression, anxiety, hypomania,
emotional lability, memory defects.
Decreased C4 in CSF in patients with CNS
involvement.
Depression is associated with antiribosomal P protein
Ab.
7. Gastrointestinal:
Anorexia, nausea, vomiting, abdominal pain.
Bowel infarction/perforation secondary to
mesentric vasculitis.
Pancreatitis, pericarditis, ascitis.
Infarction of the tongue.
Hepatomegaly, chronic active hepatitis.
Lupus hepatitis-involve mainly young women
who have a benign cirrhosis and evidence of
adrenal over activity, febrile upsets,
polyarthritis, hyper globulinemia.
8. Occular:
Conjunctivitis, episcleritis.
Blindness secondary to CRAO.
Keratoconjunctivitis Sicca.
9. Lymphatic system:
Lymphadenopathy.
Splenomegaly.
SLE in Pregnancy.
Fertility is normal if renal function is good.
Worsening of SLE is uncommon in pregnancy
especially those on immuno suppression
therapy.
Permanent deterioration of renal function
occurs in less than 10%.
There is a high risk of premature delivery,
fetal loss and perinatal mortality in all cases.
With a history of recurrent fetal loss,
treatment with prednisone and aspirin may
be effective.
Dosage of steroid should be temporarily
increased during delivery and postpartum.
If patient is on azathioprine, it should be
continued.
Estrogen containing OCP even at low doses
should be avoided in women with SLE.
Neonatal LE(NLE):
Most frequent clinical manifestations are
cutaneous lesions and congenital heart block.
Serological markers most commonly associated is
Ro, SSA Ab.
Others: La, SSB and U1 Ab.
HLA DR3.
Most common cutaneous finding is an
erythematous slightly scaly eruption of the face
and periorbital skin(Racoon sign or owl eye)
Lesions may be present at birth.
Rash improve over the first few months of life usually
without scarring.
CARDIAC-complete heart block, pericardial effusion,
pleural effusion, IUGR.
HEMATOLOGICAL-thrombocytopenia, neutropenia,
hemolytic anemia, aplastic anemia.
Hepatosplenomegaly, Cholestasis.
Few infants with NLE can develop full blown
connective tissue disease in later life.
Lab Findings
Acute phase reactants are increased in active
phases
Serum globulin increased.
Complement level decreased in active
disease.
Anemia, low serum iron, positive coomb’s
test.
Leucopenia, thrombocytopenia, increased
plasma viscosity.
False positive VDRL, Rh factor.
LE cell test is positive in more than 80%
of the patients.
LE cells are polymorpho nuclear
leucocytes which have ingested nuclear
material from degenerative white cells,
in the presence of an Ab to deoxy ribo
nucleo protein.
A broad spectrum of autoantibodies may be
found in patients with SLE. ANA are the most
sensitive.
Other autoantibodies include anti single
stranded(ss) DNA, LE cell or anticytoplasmic
(Ro/La) Ab.
Ab to native or double stranded DNA is closely
related to the risk of development of lupus
nephritis.
5 nuclear staining patternshomogeneous, particulate, speckled,
nucleolar and peripheral-are
demonstrated by fluorescent Ab
technique.
SLE patients generally show 2 or more
of these patterns.
1. Homogeneous pattern is characterized by
diffuse nuclear staining which is produced by
an Ab to DNA histone complex.
2. Particulate pattern are produced by Ab to
saline extractable nuclear antigen, which
include nuclear ribonuclear protein and the
smith antigen.
3. Speckled pattern is produced by Ab to
centromere and is highly specific for CREST
syndrome.
4. Nuclear pattern is usually present in
patients with Raynaud’s phenominon and
other scleroderma like features.
5. Peripheral or membranous or shaggy
pattern results from staining of the
periphery of the nucleus. This pattern
indicates Ab to DNA(specific to SLE).
Clinical significance of fluorescent antinuclear
antibody patterns
Pattern
Previous
Nomenclature
Associated Disease
Particulate
Speckled, thready,
fibrillar, reticular
Mixed CT ds, SLE, scleroderma, undiff.
CT ds, malignancy.
Homogenou
s
Diffuse, solid
CT ds when present in high titre,
suspect SLE
Peripheral
Shaggy, rim,
membranous
Active SLE(highly specific); common
in SLE with nephritis.
Speckled
True speckled
“pepper dots”
Scleroderma/CREST, Raynauds
phenomenon(anticentromere Ab)
Nucleolar
Large discrete
speckles
Scleroderma, Raynaud’s
phenomenon, uncommon in SLE, rare
in MCTD.
Peripheral and homogenous pattern are most
common pattern seen in SLE.
Examination of normal appearing skin by DIF
can be useful in SLE.
Cryoglobulin may be found in 11% of SLE
patients.
Other possible indicators of disease activity
include β2 macroglobulin, serum IFN, urinary
level of neopterin, IL6.
Anti nuclear Ab negative SLE.
ANA cannot be demonstrated in 5-10% of
patients with SLE, using standard substrate
such as rat or mouse liver.
This can be reduced to less than 1% if Hep-2
cells are used.
These patients frequently have Anti Ro/La Ab
and have many similarities with patients
suffering from SCLE.
Treatment of LE:
Rule out underlying SLE disease activity in patient
with any form of Cutaneous LE.
Sun protection.
Avoid photo sensitive drugs like hydrochlorthiazide,
tetracyclines, NSAID’s.
ACLE lesions usually responds to systemic
immunosuppressive measures required to treat the
underlying SLE disease activity.
Patients with SCLE & CCLE non immuno suppressive
therapy is preferred.
Local therapy:
Sunscreens.
UV blocking films for home and automobile
windows.
Topical glucocorticoid steroids-super potent
Class I agents like clobetasol propionate
0.05% or Betamethasone dipropionate
0.05% cream.
Intra lesional glucocorticoids.
Systemic treatment for Cutaneous LE:
First line:
HCQ
HCQS+Quinacrine.
Chloroquine + Quinacrine.
Second line:
Dapsone, Retinoids, Etretinate, Acetretin,
Thalidomide.
Third line:
Clofazimine, Gold.
Fourth line:
Systemic Steroids
-oral prednisolone
-IV pulse methyl prednisolone.
Azathioprine, Methotrexate, Cyclophosphamide.
ImmunotherapyHigh dose IVIG, CD4 depleting monoclonal
Ab.
Phototherapy-UVA1 phototherapy,
photopheresis.
Other drugsSulfasalazine, Phenytoin, Danazol,
Dehydroepiandrostenedione, cytosine
arabinoside, cyclosporine.
Argon and pulse dye laser for active cutaneous
LE.
Resurfacing of atrophic scars with Eb:YAG or
Co2 laser.