Systemic Lupus Erythematosus

זאבת אדמנתית מערכתיתזאבתSLELupus

דר' דפנה פארןסגנית מנהל המחלקה הראומטולוגית

בי"ח איכילוב

Systemic Lupus ErythematosusDefinition

• 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

• FCRIIA, FCRIIIA predispose to SLE in some

ethnic groups (possibly responsible for impaired IC clearing)

Q: Which of the following statements regarding genetic predisposition in SLE is incorrect?

1. ~ 10% of SLE patients have relatives with SLE

2. The concordance for monozygotic twins is 85%

3. Males need more susceptibility genes

4. Relatives of SLE patients have increased incidence of auto-antibodies

5. Relatives of SLE patients have increased incidence of other autoimmune diseases

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 ManifestationsLE-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 dermatitisThickened epidermal basement membrane (large arrows)Inflammatory infiltrates (small arrow)

Skin biopsy - Discoid lesionHyperkeratosis (small arrow)Lymphoid infiltrates (thick arrow) Fibrosis of deep dermis

F

Musculoskeletal Manifestations

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

- tenosynovitis-may be early manifestation

• Myopathy:

- myositis = true inflammation

- myopathy 2nd to drugs: steroids, anti-malarials

Jaccoud’s 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)

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

• Activity index• Chronicity Index

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

Question

A 40 year old woman with a 20 year history of SLE presents with:chest pain, dyspnea and fever.

Current medications: Prednisone 10mg, Methotrexate 15 mg/wk, Plaquenil 400mg/d

Which of the following are a possible diagnosis? 1. Pneumonia2. Pleuritis / Pericarditis3. Lupus pneumonitis4. Pulmonary embolism5. All of the above

Hematologic Manifestations

• Anemia: - in acute SLE:

coomb’s 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

- 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 RheumatologyNomenclature and case definitions for Neuropsychiatric lupus syndromes . Arthritis & Rheumatism 1999

Question

A 35 year old woman with a 5 year history of SLE

Currently on: Prednisone 40mg/d, Azathioprine 100mg/d

Presents to the E.R with:• Fever • Acute confusional state • Focal neurological findings

How would you manage her?

1. Give her a sedative due to agitated/confused state

2. Give her IV Antibiotics

3. Give her pulse IV Solumedrol 1000mg

4. Perform a brain CT scan and lumbar puncture

5. Give her Heparin

What does the differential diagnosis include?

• Infection - meningitis/ encephalitis • Active CNS Lupus

• Toxic \ Metabolic

• Thromboembolic

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

ANA’s 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

ANAs 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%

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 FREQUENCY % SPECIFICITY CLINICAL SUBSET

dsDNA 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

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 Criterion1. Malar Rash2. Discoid rash

3. Photosensitivity4. Oral ulcers5. Arthritis6. Serositis7. Renal disorder

8. Neurologic disorder

9. Hematologic disorder

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

Classification criteria of 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 inabsence of drugs known to cause DIL

For diagnosis: any 4 of 11 criteria

Drug Induced Lupus

• Clinical manifestations of SLE that: - appear while taking a drug

- resolve on discontinuation of the drug • 10% of the incidence of SLE

• Clinical features are less severe than SLE.

• Common features: fatigue, weight loss, fever, arthritis, serositis, cytopenias.

• Uncommon features: CNS and renal involvement

Drug Induced Lupus

• ANA-positive

• Anti-Histone - positive in > 90% nonspecific - found in SLE as well • Anti-DNA - negative

• complement usually normal

• serology resolves slowly on drug discontinuation

Drugs associated with Drug Induced Lupus

• Definite: Hydralazine (5-10%) , Procainamide (15-20%), Chlorpromazine, Methyldopa, Isoniazid

• Possible association: Phenytoin, Penicillamine, Quinidine

• Questionable association: Gold salts, Griseofulvin

Management of SLE

The Challenge

• Treat Active Lupus

• Prevent Damage from:

- Active lupus

- Corticosteroids

- Immunosuppressive agents

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

Treatments for SLE

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

• 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 1gr methylprednisolone sometimes used for refractory nephritis or life threatening disease

Anti-MalarialsHydroxychloroquine, 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

• 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

Immunosuppressive agentsAzathioprine, Cyclophosphamide, Cyclosporine, Cellcept

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) 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

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

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 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

Corticosteroids- the price:

• Avascular Necrosis of Bone

• Osteoporosis with Fracture

• Hypertension, Hyperglycemia

• Premature Atherosclerosis

• Quality of life: Weight, Cushingoid Habitus, Mood changes

Distribution of DamageJohns Hopkins Cohort

• 25.2% musculoskeletal• 15.0% neuropsychiatric• 12.6% ocular• 11.7% renal• 10.4% pulmonary• 10.1% cardiovascular• 7.4% gastrointestinal• 7.4% skin

• 6.1% diabetes• 2.5% malignancy• 1.2% premature

gonadal

failure

SLICC Damage Index

• SLICC:

Systemic Lupus International Collaborating Clinics

• Damage = nonreversible change not related to active inflammation, present for 6 months

Damage in SLE - Coronary Artery Disease

• Major cause of morbidity

• Bimodal pattern of mortality in SLE:

early - due to disease and infection

late - due to Cardiovascular disease

• prevalence: 8-10%

• Hydroxychloroquine- may be protective:

reduces cholesterol, anti-aggregation properties

Prevalence of cardiovascular disease in SLE

• Hospitaliztion of young SLE women compared to non SLE:

- 2-3 times more likely to have MI

- 3.8 times more likely to have CHF

- 2.1 times more likely to have CVA

• SLE women age 35-44: 50 times more likely to have MI compared to women of similar age (Framingham offspring study)

Risk factors for cardiovascular disease in SLE

• Hypertension

• Hyperlipidemia

• Diabetes Mellitus

• Obesity

• Active SLE:

- chronic inflammation leads to endothelial damage

- anti-endothelial abs, anti-phospholipid antibodies

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

Q: Which statement is incorrect regarding pregnancy in lupus1. SLE patients are less fertile ( low fertility rate)

2. SLE patients have higher frequency of premature labor.

3. SLE may flare during pregnancy and postpartum

4. Neonatal lupus occurs due to transplacental transmission of maternal auto-abs

5. Most well controlled lupus patients can become pregnant and give birth to healthy children

Pregnancy Outcomes in SLE Johns Hopkins Cohort

• 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

• 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

Neonatal Lupus

1. Neonatal cutaneous lupus2. Congenital heart block • Due to placental transmission of maternal IgG abs

• Occurs in women with: - anti Ro\SSA , anti La\SSB, anti U1 RNP

• Prevalence of neonatal lupus in mothers with the auto-abs: 2-5%

• The mother may be : asymptomatic, have: SLE, Sjogren syn,

other rheumatic disease.

Neonatal cutaneous lupus

Congenital heart block (CHB)

• Prevalence: 1:20,000 births ( 0.005%)

• anti Ro \ anti La + should have weekly echocardiographies at 18-25 weeks

• complete block: in 90% of reported cases

• 60% require pacemakers, 30%-die

• recurrence - 13%

Management of congenital heart block

• Prophylactic treatment of high risk mother - not helpful.

• Treatment of identified block: T. Dexamethasone 4mg\d

• Rationale for treatment of identified block: - reduce generalized inflammatory insult

- lower titer of maternal auto-abs.

Female, 19 years old single, Israeli born

1995:• Fever• Sore throat• Polyarthritis• Systolic murmur 2/6

Initial working diagnosis: Rheumatic Fever

History and laboratory work-up

• Weight loss, fatigue• Hair loss for past months, photosensitive rash • Raynaud’s phenomenon

Lab:• ANA +, anti-DNA - 30%, low C3• CBC, chemistry, urine - normal• anti-cardiolipin IgG -positive• lupus anticoagulant- positive

Echocardiogram: mild mitral regurgitation

Treatment and Course

• Plaquenil 200 mg x 2\d• Naxyn 500 mg X 2\d

• nearly asymptomatic for 1 year

1996: Flare

• Polyarthritis• elevated anti-DNA ( 87%)• low complement• microscopic hematuria, RBC casts, proteinuria:

1.7 gr/24 hrs• preserved CCT

• Kidney biopsy:

focal proliferative glomerulonephritis ( Class III)

Treatment

• T. Prednisone 60 mg\d

• IV Cyclophosphamide 500mg\m2

- once a month for 6 months

- once every 3 months

• Continue: Plaquenil 200mg x 2\d

Course

Initial response:

• resolution of arthritis and proteinuria

• persistent hematuria

• normalization of C3 C4, drop in anti-DNA (22%)

• prednisone dose tapered to 12.5 mg\d

1997: Flare 1 week prior to 8th CTX pulse

• Polyarthritis

• severe nephrotic syndrome: proteinuria: 11gr\24hrs albumin: 2.0 gr\dl

microscopic hematuria

• drop in complement

• rise in anti-DNA - 45%

Histologic class transformation?

• Repeat kidney biopsy- suggested but not done due to:

• non- occluding Renal Vein Thrombosis

• 2 episodes of pleuritic chest pain- suspected Pulmonary embolism

Treatment

• IV Heparin, followed by Warfarin ( INR-2.5)

• IV pulse Methylprednisolone 1 gr\d for 3 days followed by Prednisone 60 mg\d

• IV pulse Cyclophosphamide 800 mg\m2 once a month

Course

• Gradual improvement in proteinuria - 2 gr\24 hrs• normalization of anti-DNA, increase in C3 C4• Avascular necrosis - both knees, both shoulders

after 3 months:• Cyclophosphamide switched to Azathioprine• Prednisone tapered to 15 mg\d

1998: Flare

• Pancytopenia• Nephrotic syndrome:

- protein 5.5 gr\24hrs - albumin 1.2 gr\dl - anasarca

Treatment:• IV pulse methylprednisolone 1 gr/ 3 days• IV cyclophosphamide 1000 mg/m2

Course

• Neutropenic fever - post cyclophosphamide

- resolved with antibiotics

• No improvement in proteinuria or activity of disease.

Management??

Treatment

• Supportive: IV salt free albumin

high dose diuretics

ACE inhibitors

• Cyclosporine - 5 mg\kg

• Prednisone - 60 mg\d

Course

Gradual marked improvement:

• resolution of pancytopenia

• resolution of proteinuria, normalization of albumin

• normalization of anti-DNA and complement

• persistent microscopic hematuria

Problems

• unable to reduce prednisone below- 12.5 mg\d

• unable to reduce cyclosporine doses

• Azathioprine added as steroid sparing and “cyclosporine sparing”

Course

• Remission for 18 months no proteinuria, normal anti DNA, C3, C4• Planned pregnancy

• Treatment during pregnancy: Plaquenil, Azathioprine, Prednisone 10mg\d Low molecular weight Heparin

• Delivered healthy baby at term• Mild flare 2 months postpartum: proteinuria < 1 gr\d • Controlled with prednisone