SYSTEMIC LUPUS ERYTHEMATOSUS - AN OVERVIEW

- Dr. Parvez Khan - Dr. Deepak Kapoor

Assistant Professors, M - 1 Department of Internal Medicine Deccan College of Medical Sciences

Systemic Lupus Erythematosus

Definition
An inflammatory multi-system disease Immunologic aberrations:

excessive auto-antibody production

Tissue damage results from antibody and

complement fixing immune complex deposition

Wide spectrum of clinical presentations Characterized by remissions and exacerbations

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

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

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

Genetic Epidemiology
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 some

ethnic groups
(possibly responsible for impaired IC clearing)

Genetic Epidemiology
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

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

Environmental Factors
Ultraviolet light ( UVB ) Alfalfa sprouts, chemicals ( hydrazines) ? Drugs (Resprim = Trimethoprim + sulphamethoxazole)

Infections (parvovirus, CMV, HCV )

Smoking ( Discoid LE )

Defective Immune Regulation

B cell and T cell hyperactivity leads to:

T cell dependent auto-Ab production made in high quantity

Subsets of auto-Abs and the Immune

Complexes they form with Ag mediate tissue damage

Defective clearance of Immune Complexes Defects in immune tolerance and apoptosis

Defects in T and natural killer regulatory cells

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)

Clinical Manifestations of SLE

Constitutional non-specific but very common: - Fatigue - Fever - Weight Loss

Skin Manifestations
LE-specific lesions

Acute:
- malar butterfly rash - generalized erythema - bullous LE

Subacute cutaneous lupus Chronic lupus:

- localized discoid

- generalized discoid - lupus profundus

Butterfly- malar rash

Generalized, photosensitive erythema

Bullous rash

Subacute cutaneous rash

psoriatiform annular

Discoid rash

Skin Manifestations
LE-nonspecific lesions

Panniculitis Urticarial lesions Vasculitis Livedo reticularis Oral lesions Non-scarring alopecia

Panniculitis

Vasculitis with finger tip ulcers

Livedo reticularis

Alopecia

(diffuse or patchy)

Non-scarring if part of SLE flare Scarring if results from discoid

Skin biopsy:
Lupus band test = immunofluorescent staining of IgG and complement deposits in dermo-epidermal junction

Skin biopsy - SLE dermatitis

Thickened epidermal basement membrane (large arrows) Inflammatory infiltrates (small arrow)

Skin biopsy - Discoid lesion

Hyperkeratosis (small arrow) Lymphoid infiltrates (thick arrow) Fibrosis of deep dermis

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

Jaccouds arthropathy

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

WHO Classification of Lupus Nephritis

J Am Soc Nephrol 15: 241-250, 2004

Class I - Minimal mesangial LN

(mesangial immune deposits seen by IF)

Class II - Mesangial proliferative LN Class III- Focal proliferative LN

(<50% of glomeruli with focal subendothelial immune deposits)

Class IV - Diffuse proliferative segmental LN (IV-S)

- Diffuse proliferative global LN

(IV-G)

(> 50% of glomeruli with subendothelial immune deposits)

Class V - Membranous LN
(global or segmental subepithelial deposits) Activity index Chronicity Index

Class VI - Advanced sclerosing LN

(> 90% of glomeruli globally sclerosed)

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

Serositis in SLE
Pleuritis - occurs in 30-60% of patients Pericarditis - occurs in 20-30% Peritonitis

Cardiac Manifestations
Pericarditis
Myocarditis Endocarditis (Libman -Sacks endocarditis)

Coronary heart disease

Pulmonary Manifestations
Pleuritis Pneumonitis - acute or chronic Pulmonary hemorrhage - due to vasculitis

Pulmonary hypertension
Pulmonary embolism

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

Hematologic Manifestations
Thrombocytopenia: - anti-platelet abs- common, not always associated with thrombocytopenia

- occurs in active SLE

- may be isolated finding ( ~ 50,000 without serious bleeding )

Neuropsychiatric SLE
Central nervous system
-

Peripheral nervous system

- Guillain - Barre syndrome - Autonomic disorder - Mononeuropathy, -

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

single/multiplex Myasthenia Gravis Neuropathy, cranial Plexopathyy Polyneuropathy

The American College of Rheumatology Nomenclature and case definitions for Neuropsychiatric lupus syndromes . Arthritis & Rheumatism 1999

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

Patterns of IF ANA staining

Homogenous (diffuse) - dsDNA, histone

SLE, drug induced SLE, RA

Speckled
MCTD, SLE, Sjogren, Systemic Sclerosis

Nucleolar
Systemic Sclerosis, Sjogren, SLE

Rim (peripheral) - dsDNA histones

characteristic of SLE

Patterns of Immuno-fluorescence ANA staining

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

AUTOANTIBODIES IN SLE:
Autoantibody

Prevalence

anti- ds DNA anti- ss DNA anti- Histones anti- Sm ( Smith) anti- RNP anti- Ro ( SSA) anti- La ( SSB)

50-60% 60-70% 70% 30% 35% 30% 15%

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 direct binding to glomeruli or immune-complex mechanisms.

Clinical Associations of Auto-antibodies in SLE

ANTIBODY dsDNA ssDNA Histones Ro La Sm RNP FREQUENCY % SPECIFICITY 50-60 60-70 70 30 15 30 10 ++ + + + ++ + Drug-induced LE Subactue cutaneous Lupus, Heart block Nephritis,CNS MCTD Thrombosis Recurrent fetal loss CLINICAL SUBSET Nephritis

Antiphospholipid 30-40 antibodies

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

Classification criteria of SLE

Criterion 1. Malar Rash 2. Discoid rash
3. 4. 5. 6. 7. 8.
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 OR cellular casts - Seizures OR Psychosis - Hemolytic anemia OR Leukopenia < 4000/ mm3 OR Lymphopenia <1500/mm3 OR Thrombocytopenia < 100.000/mm3

Photosensitivity Oral ulcers Arthritis Serositis Renal disorder

Neurologic disorder 9. Hematologic disorder

Classification criteria of SLE

Criterion 10. Immunologic disorder Definition - anti-dsDNA OR - anti- Sm OR - false positive VDRL / anti-phospholipid antibody

11. Anti-nuclear antibody

Abnormal titer of ANA in absence of drugs known to cause DIL

For diagnosis: any 4 of 11 criteria

MANAGEMENT OF SLE

The Challenge
Treat Active Lupus Prevent Damage from:

- Active lupus - Corticosteroids - Immunosuppressive agents

Treatment of active SLE

Organ 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

Treatments for SLE

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

Antimalarials

Methotrexate Azathioprine Cyclophosphamide Cyclosporine Mycophenolate Mofetil (Cellcept)

IVIG Thalidomide

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 anemia or thrombocytopenia

IV pulse 1g methylprednisolone sometimes used

for refractory nephritis or life threatening disease

Corticosteroids- the price:

Avascular Necrosis of Bone Osteoporosis with Fracture Hypertension, Hyperglycemia Premature Atherosclerosis Quality of life: Weight, Cushingoid Habitus, Mood changes

Anti-Malarials
Hydroxychloroquine, Chloroquine, Quinacrine

Effective for the treatment of :

Fatigue, Arthritis, Skin disease

Prevents SLE flares
Lowers cholesterol levels Anti-aggregant effect

Methotrexate
May be effective as a steroid sparing agent in the treatment of:

- arthritis - skin disease

Immunosuppressive agents
Azathioprine, 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 2-3 yrs - Cyclosporine: P.O. 1-3mg\kg\d - Mycophenolate Mofetil (Cellcept) : P.O. 1-3gr\d

Treatment of Lupus Nephritis

Induction: - Corticosteroids - IV Cyclophosphamide \ q month

- Mycophenolate Mofetil (Cellcept) ?

Maintenance:

- IV Cyclophosphamide \ q 3 mo - Azathioprine - Mycophenolate Mofetil ( Cellcept ) - Cyclosporine

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)

Immunosuppressive for:

kidney, liver and heart transplant

Inhibitor of :

Inosine Monophosphate (IMP) dehydrogenase - key enzyme in de novo purine 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

Ginzler et al. NEJM 2005

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

MMF (71 pts) At 12 weeks: - Complete remission - Partial remission: - Death - Severe infections - Diarrhea 16 21 0 1 15 CTX (69 pts) 4 17 3 6 2

Conclusion: - MMF more effective than CTX in inducing remission - severe infections : less with MMF

Sequential Therapies for proliferative LN

Contreras 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

Future possible treatments for SLE

Treatments 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 B
cells

Anti C5 complement C1q immunoadsorption:

removes immune complexes

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

depletion

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

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

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

Pregnancy Outcomes in SLE

Johns Hopkins Cohort
Fertility rates: normal 2-2.4 pregnancies\patient

Preterm < 37 weeks < 36 weeks

Pregnancy loss 1st trimester

40.5% 32.1% 10-30% 6.0% 7.1%

2nd trimester

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

Management of SLE flares in pregnancy

Prednisone
IV Pulse methylprednisolone NSAIDs ( during 1st trimester ) Plaquenil Azathioprine

Cyclosporine

THANK YOU