SLE - Overview

7/30/2019 SLE - Overview

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SYSTEMIC LUPUS ERYTHEMATOSUS

- AN OVERVIEW

- Dr. Parvez Khan- Dr. Deepak Kapoor

Assistant Professors, M - 1

Department of Internal MedicineDeccan College of Medical Sciences


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Systemic Lupus ErythematosusDefinition

An inflammatory multi-system disease

Immunologic aberrations:excessive auto-antibody production

Tissue damage results from antibody andcomplement fixing immune complex deposition

Wide spectrum of clinical presentations

Characterized by remissions and exacerbations


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Epidemiology

SLE - recognized worldwide

Prevalence in USA: 15-50 \ 100,000 (1:2000)

Incidence in USA: 1.8-7.6 \ 100,000\ year

F:M 9:1 ( at age: 14-64 )

Racial predisposition:

x 3 more common in blacks


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Epidemiology in the young and elderly

Peak incidence is at age 15-40

But: Onset may be at any age

In pre-pubertal and post menopausal:

female : male ratio 3:1


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Genetic Epidemiology

SLE is a multi-genic disease

In < 5% of patients a single gene is responsible

Homozygous deficiencies of early components

of complement (C1q, C1r, C1s, C4, C2)

predispose to SLE

A null allele for C4A is the HLA-linked gene most

consistently associated with susceptibility to SLE


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HLA class II genes are associated with

production of auto-antibodies

TCR genes and Ig genes may contribute to

susceptibility

FCgRIIA, FCgRIIIA predispose to SLE in someethnic groups

(possibly responsible for impaired IC clearing)


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concordance for monozygotic twins: 24-58%

relatives of SLE patients have increased incidence of:

- SLE

- other auto-immune diseases

- auto-antibodies

~ 10% of SLE patients have relatives with SLE

males need more susceptibility genes


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Importance of Sex hormones

Female predominance (9:1)

disease activity during menstrual period

increased disease activity in pregnancy

flares with oral contraceptive therapy

abnormally rapid testosterone metabolism

estrogenic metabolites persist longer


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Environmental Factors

Ultraviolet light ( UVB )

Alfalfa sprouts, chemicals ( hydrazines) ?

Drugs (Resprim = Trimethoprim + sulphamethoxazole)

Infections (parvovirus, CMV, HCV )

Smoking ( Discoid LE )


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Defective Immune Regulation

B cell and T cell hyperactivity leads to:

T cell dependent auto-Ab production made inhigh quantity

Subsets ofauto-Abs and the Immune

Complexes they form with Ag mediate tissuedamage

Defective clearance of Immune Complexes

Defects in immune tolerance and apoptosis

Defects in T and natural killer regulatory cells


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Pathogenic auto-antibodies

Mechanisms of damage

Direct binding to tissue via charge or

cross-reactivity ( anti-DNA)

Production of Immune Complexes leads to

complement mediated damage

Direct binding to cell membranes

( RBCs, Platelets)


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Clinical Manifestations of SLE

Constitutional

non-specific but very common:

- Fatigue

- Fever

- Weight Loss


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Skin ManifestationsLE-specific lesions

Acute:- malar butterfly rash

- generalized erythema

- bullous LE

Subacute cutaneous lupus

Chronic lupus:

- localized discoid

- generalized discoid

- lupus profundus


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Butterfly- malar rash


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Generalized, photosensitive erythema


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Bullous rash


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Subacute cutaneous rash

psoriatiform annular


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Discoid rash


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Skin ManifestationsLE-nonspecific lesions

Panniculitis

Urticarial lesions

Vasculitis Livedo reticularis

Oral lesions

Non-scarring alopecia


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Panniculitis


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Vasculitis with finger tip ulcers


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Livedo reticularis


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Alopecia (diffuse or patchy)

Non-scarring if part of SLE flare

Scarring if results from discoid


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Skin biopsy:Lupus band test = immunofluorescent staining of

IgG and complement deposits indermo-epidermal junction


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Skin biopsy - SLE dermatitisThickened epidermal basement membrane (large arrows)

Inflammatory infiltrates (small arrow)


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Skin biopsy - Discoid lesionHyperkeratosis (small arrow)

Lymphoid infiltrates (thick arrow)

Fibrosis of deep dermis

F


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Musculoskeletal Manifestations

Arthritis:- the most common manifestation of SLE- non-erosive, rarely deforming (Jaccouds deformity)- synovial fluid- mild inflammation

- tenosynovitis-may be early manifestation

Myopathy:

- myositis = true inflammation- myopathy 2nd to drugs: steroids, anti-malarials


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Jaccouds arthropathy


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Renal Disease in SLE

Proteinuria: 0.5 gr\ 24 hrs ( or > +3 )

Urinary casts: RBC,granular,tubular,mixed

Hematuria: > 5 RBC / high power field

Pyuria: > 5 WBC / high power field

prevalence: 30-65%

in 3-6% renal disease is first manifestation


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WHO Classification of Lupus NephritisJ Am Soc Nephrol 15: 241-250, 2004

Class I - Minimal mesangial LN(mesangial immune deposits seen by IF)

Class II - Mesangial proliferative LN

ClassIII- Focal proliferative LN( 50% of glomeruli with subendothelial immune deposits)

Class V - Membranous LN(global or segmental subepithelial deposits)

Class VI - Advanced sclerosing LN(> 90% of glomeruli globally sclerosed)

Activity index

Chronicity Index


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Renal disease in SLE

Mild disease - Class II Serious disease - Class III, IV, V

Clinical course:

- Class II:hematuria, sub-nephrotic proteinuria, preserved GFR

- Class III and IV:edema, HTN

nephritic sediment, mild-mod proteinuria, acute GFR

- Class V:features of nephrotic syndrome, preserved/ gradual GFR


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Serositis in SLE

Pleuritis - occurs in 30-60% of patients

Pericarditis - occurs in 20-30%

Peritonitis


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Cardiac Manifestations

Pericarditis

Myocarditis

Endocarditis (Libman -Sacks endocarditis)

Coronary heart disease


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Pulmonary Manifestations

Pleuritis

Pneumonitis - acute or chronic

Pulmonary hemorrhage - due to vasculitis

Pulmonary hypertension

Pulmonary embolism


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Hematologic Manifestations

Anemia:- in acute SLE:

coombs positive hemolytic anemia

- secondary to:

chronic disease, CRF, blood loss, drugs.

Leukopenia / Lymphopenia:- in active disease

- secondary to drugs, infection


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Hematologic ManifestationsThrombocytopenia:

- anti-platelet abs- common, not always

associated with thrombocytopenia

- occurs in active SLE

- may be isolated finding

( ~ 50,000 without serious bleeding )


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Neuropsychiatric SLE

Central nervous system

- Aseptic meningitis- Cerebrovascular disease- Demyelinating syndrome- Headache (migraine, benign

intracranial pressure)- Movement disorder (chorea)- Myelopathy- Seizure disorder- Acute confusional state- Anxiety disorder- Cognitive dysfunction- Mood disorder- Psychosis

Peripheral nervous system

- Guillain - Barre syndrome- Autonomic disorder- Mononeuropathy,

single/multiplex- Myasthenia Gravis- Neuropathy, cranial- Plexopathyy- Polyneuropathy

The American College of Rheumatology

Nomenclature and case definitions for

Neuropsychiatric lupus syndromes .

Arthritis & Rheumatism 1999


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Anti-Nuclear Antibodies (ANA)

ANA : abs directed against nuclear antigens

may occur in other systemic rheumatic diseases

most frequent and highest in titer in SLE

Positive in 98% of SLE patients

detected by indirect immuno-fluorescence


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Patterns of IF ANA staining

Homogenous (diffuse) - dsDNA, histoneSLE, drug induced SLE, RA

Speckled

MCTD, SLE, Sjogren, Systemic Sclerosis

Nucleolar

Systemic Sclerosis, Sjogren, SLE

Rim (peripheral)- dsDNA histones

characteristic of SLE


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Patterns of Immuno-fluorescence ANAstaining


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ANAs

ANAs can be divided into:

those directed against dsDNA

those directed against ssDNA

those directed against histones

those directed against non-histone nuclear proteins :nucleic acid-protein complexes


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AUTOANTIBODIES IN SLE:

Autoantibody

anti- ds DNA

anti- ss DNA

anti- Histones anti- Sm ( Smith)

anti- RNP

anti- Ro ( SSA)

anti- La ( SSB)

Prevalence

50-60%

60-70%

70% 30%

35%

30%

15%


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Anti DNA antibodies in SLE

Anti ss- DNA:nonspecific and not in clinical use

Anti-ds DNA: specific for SLE

Clinical use important:- levels correlate with disease activity- presence and level associated with risk for

renal disease

- pathogenic effect mediated through directbinding to glomeruli or immune-complexmechanisms.


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Clinical Associations of Auto-antibodies in SLE

ANTIBODY FREQUENCY % SPECIFICITY CLINICAL

SUBSETdsDNA 50-60 ++ Nephritis

ssDNA 60-70 -

Histones 70 + Drug-induced LE

Ro

La

30

15

+

+

Subactue

cutaneous Lupus,

Heart block

Sm 30 ++ Nephritis,CNS

RNP 10 + MCTD

Antiphospholipid

antibodies

30-40 Thrombosis

Recurrent fetal

loss


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Diagnosis of SLE

Based on a combination of clinical

manifestations and laboratory findings

which may occur simultaneously or serially

Classification criteria are used for research

Cl ifi ti it i f SLE


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Classification criteriaof SLECriterion

1. Malar Rash

2. Discoid rash

3. Photosensitivity

4. Oral ulcers

5. Arthritis6. Serositis

7. Renal disorder

8. Neurologicdisorder

9. Hematologicdisorder

Definition- Fixed erythema, malar distribution- Erythematous raised patches with

scaling, atrophy, scarring- Skin rash as result of sunlight- Oral\ nasopharyngeal, usually painless- Nonerosive, 2 or more joints

- Pleuritis OR Pericarditis-Proteinuria > 0.5gr or >+3 ORcellular casts

- Seizures OR Psychosis

- Hemolytic anemia ORLeukopenia < 4000/ mm3 ORLymphopenia


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Classification criteriaof SLE

Criterion10. Immunologic disorder

11. Anti-nuclear antibody

Definition- anti-dsDNA OR

- anti- Sm OR

- false positive VDRL /

anti-phospholipid antibody

Abnormal titer of ANA in

absence of drugs known tocause DIL

For diagnosis: any 4 of 11 criteria


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MANAGEMENT OF SLE


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The Challenge

Treat Active Lupus

Prevent Damage from:

- Active lupus

- Corticosteroids

- Immunosuppressive agents


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Treatment of active SLEOrgan System Approach

Use the drug with the:

- Least side effects

- Lowest dose to control disease

- Long term damage prevention

Mild disease: Avoid Steroids

Severe disease: Aggressive treatment

T t t f SLE


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Treatments for SLE

NSAIDs

Corticosteroids Hydroxychloroquine (Plaquenil) Chloroquine (Aralen) Antimalarials Quinacrine ( Mepacrine; Atabrine)

Methotrexate Azathioprine Cyclophosphamide Cyclosporine

Mycophenolate Mofetil (Cellcept)

IVIG Thalidomide

C ti t id


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Corticosteroids

Effective for the suppression of all SLE

manifestations

NOT justified for Arthritis

Moderate doses (20-30mg/d) sufficient for:pleuritis/pericarditis

High doses (1mg/kg) required for:

Nephritis, CNS disease, Severe hemolytic anemiaor thrombocytopenia

IV pulse 1g methylprednisolone sometimes usedfor refractory nephritis or life threatening disease


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Corticosteroids- the price:

Avascular Necrosis of Bone

Osteoporosis with Fracture

Hypertension, Hyperglycemia

Premature Atherosclerosis

Quality of life:

Weight, Cushingoid Habitus, Mood changes


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Anti-MalarialsHydroxychloroquine, Chloroquine, Quinacrine

Effective for the treatment of :

Fatigue, Arthritis, Skin disease

Prevents SLE flares

Lowers cholesterol levels

Anti-aggregant effect


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Methotrexate

May be effective as a steroid sparing agent in

the treatment of:

- arthritis

- skin disease


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Immunosuppressive agentsAzathioprine, Cyclophosphamide, Cyclosporine, Cellcept

Used mainly for nephritis

May be used for major organ involvement

-Azathioprine: P.O. 2-3mg\kg- Cyclophosphamide :

IV pulses 0.5-1.0gr/m2 q month than q3 months for 2-3yrs

- Cyclosporine: P.O. 1-3mg\kg\d

- Mycophenolate Mofetil (Cellcept) : P.O. 1-3gr\d


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Treatment of Lupus Nephritis

Induction:-Corticosteroids- IV Cyclophosphamide \ q month

- Mycophenolate Mofetil (Cellcept) ?

Maintenance:

- IV Cyclophosphamide \ q 3 mo

- Azathioprine- Mycophenolate Mofetil ( Cellcept )

- Cyclosporine


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Cyclophosphamide side effects

Infection- frequency - 45%

- sequential infusions

- WBC < 3000

Premature ovarian failure

- cumulative dose

- age: < 25 yrs - 6%

> 31 yrs - 67%

Malignancy

leukemia, gynecologic malignancies, bladder

Mycophenolate Mofetil ( MMF = Cellcept)


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Mycophenolate Mofetil( MMF = Cellcept) Immunosuppressive for:

kidney, liver and heart transplant

Inhibitor of :Inosine Monophosphate (IMP) dehydrogenase

-key enzyme in de novopurine synthesis- glycosylation of adhesion molecules in T and B cells

Inhibits:- proliferation of T and B lymphocytes- production of abs- generation of cytotoxic T cells- recruitment of leukocytes to sites of inflammation

MMF or IV Cyclophosphamide for Lupus Nephritis


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MMF or IV Cyclophosphamide for Lupus NephritisGinzler et al. NEJM 2005

140 pts class III, IV, V (24 week trial)

MMF (71 pts) CTX (69 pts)

At 12 weeks:

- Complete remission 16 4

- Partial remission: 21 17

- Death 0 3

- Severe infections 1 6

- Diarrhea 15 2

Conclusion:

- MMF more effective than CTX in inducing remission

- severe infections : less with MMF

S ti l Th i f lif ti LN


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Sequential Therapies for proliferative LNContreras G et al. NEJM 2004

59 patients: class: III-12; IV-46; Vb-1

Induction:

IV CYC (0.5-1gr/m2) q mo for up to 7 pulses + steroids

Maintenance (1-3 yrs):

- IV CYC q 3 months

- AZA 1-3 mg/kg/d

- MMF 0.5-3 gr/d


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Future possible treatments for SLETreatments designed to effect specific processes

LJP 394: B cell toleragen: cross links anti-DNA receptors on B cells

Anti IL-10: IL-10 is increased on correlates with disease activity

Anti-CD40 ligand: prevents T cell activation

CTLA4Ig: blocks CTLA4 on activated T cells from binding to B7 on Bcells

Anti C5 complement

C1q immunoadsorption: removes immune complexes

Anti CD 20 (Rituximab):CD20 is B cells restricted ag- leads to B celldepletion

Anti-BLyS:anti B Lymphocyte Stimulator protein which is elevated in SLE

Prognosis


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Prognosis

Survival:

90-95% at 2 years 82-90% at 5 years

71-80% at 10 years

63-75% at 20 years

Poor prognostic factors:

- creatinine, nephrotic syndrome

- hypertension- thrombocytopenia

- African- American race

- low socioeconomic status


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Pregnancy and SLE

1950s:

- in SLE: pregnancy is not advised

- termination should be offered

1990s:

- 10-30% flare during pregnancy / postpartum

- most flares are minor

P O t i SLE


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Pregnancy Outcomes in SLEJohns HopkinsCohort Fertility rates: normal

2-2.4 pregnancies\patient

Preterm< 37 weeks 40.5%< 36 weeks 32.1%

Pregnancy loss 10-30%1st trimester 6.0%

2nd trimester 7.1%

The Mother in SLE


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The Mother in SLE

Risk factors for exacerbation:

- active disease 3-6 months before conception

- pre-existing renal disease

Conception during remission:10-30% risk of flare.

Mild lupus rarely exacerbates in pregnancy

Severe exacerbations: in 20% of pregnancies


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Management of SLE flares in pregnancy

Prednisone

IV Pulse methylprednisolone

NSAIDs ( during 1st trimester )

Plaquenil

Azathioprine

Cyclosporine


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