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.

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 thesecond 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.

Gilliam classification …Gilliam classification …

1. Malar Rash2. Discoid Rash3. Photo sensitivity4. Oral ulcer5. Arthritis6. Serositis7. Renal disorder8. Neurologic disorder9. Hematologic disorder10. Immunologic disorder11. Anti Nuclear antibodies

Revised ARA Criteria

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 antibodyb. Splicesome – anti Sm & anti RNP

Asc. 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, B8SCLE – 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 involvementHydralazine: 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 patternDo 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 syphilisHypertrophic 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 FORMSLE 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.

Histopathology of LE …Histopathology of LE …

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 LEDermal 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. ACLE- TEN like ACLE2. SCLE: TEN like SCLE Vesiculo bullous annular SCLE3. 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 infectionseptic 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.

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)

Neonatal LE(NLE):

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 phasesSerum 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 patterns-homogeneous, 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.

Homogenous

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.Immunotherapy-

High dose IVIG, CD4 depleting monoclonal Ab.Phototherapy-UVA1 phototherapy, photopheresis.

Antimalarials …Antimalarials …

• HCQ : 200mg BID (5-7mg/kg/d)

• Chloroquin : 250-500 mg qd (4mg/kg/d)

• Quinacrine : 100-200 mg qd

• Mechanism :

Inhbn Ag processing? cytokine (IL 1, 6,TNFα)

Impedes formation of IC PG antagonism( Inh phospholipase A )

UV light absorption

?estrogen production &

lymphocyte apoptosis

Other drugs ….Other drugs ….

Stabn lysosomal enzyme

?prodn reactive oxidants100-300 mg/dClofazimine

Stabn lysosomal membrane

?TNFα, ? N chemotaxis100-400 mg/dThalidomide

Inh alternate complement action

Inh PMNL cytotoxicity & superoxide generation

100 mg QIDDapsone

Inh collaginase & PGE2 epidermal cell diff

40 mg BD

20 -50 mg OD

Retinoids

Other drugs ….Other drugs ….

Inh DHF reductase7.5 – 30 mg /wk

MTX

Inh IMPDH1-2 g/dayMycophenolate

mofetil

Inh of calcineurin2.5-5 mg/kg/dCyclosporine

Purine analog2-2.5mg/kg/dAzathioprine

Suppresses B > T cells1-5mg/kg/dayCyclophospho

Mide

Emerging therapeutic strategiesEmerging therapeutic strategies

• Anti B cell

• Anti T cell

• Disruption of B & T cell interactions

• Cytokine inhibition

• Targeting of end effector autoimmune mechanisms

Emerging therapeutics …Emerging therapeutics …

Eculizumab

(mAb blocks C5a/C5b-9 prodn)

End effector stage

Anti –IL-10 mAb,anti-IL-6 mAb,

TNF-α Inhr,IL-1 receptor agonist

Cytokine

Inhibition

CTLA4-IgG4m,Ruplazimab

IDEC-131 (anti-CD 40L mAb)

B & T cell interaction

Anti CD4 mAbT Cell

Rituximab,Lymphostat B,TACI-Ig

LJP394

B cell

Other drugs-Sulfasalazine, 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.