Systemic Lupus Erythematosus

Mohammad Ilyas, M.D.Assistant Clinical Professor

University of Florida /Health Sciences Center

Jacksonville, Florida USA

QUIZ

THE LUPUS IS A LATIN WORD MEAN

A.Crocodile

B.Wolf

C.Sheep

D.Snake

INTRODUCTION

Systemic lupus erythematosus (SLE) is the prototypic multisystem autoimmune disorder with a broad spectrum of clinical presentations encompassing almost all organs and tissues.

The extreme heterogeneity of the disease has led some investigators to propose that SLE represents a syndrome rather than a single disease.

HISTORY 1. The term ‘lupus’ (Latin for ‘wolf’) was first used during the Middle Ages

to describe erosive skin lesions evocative of a ‘wolf’s bite’.

2. The butterfly metaphor - Viennese physician Ferdinand von Hebra 1846

3. “Lupus erythematosus - Atlas of Skin Diseases in 1856.

4. Systemic disease with visceral manifestations by Moriz Kaposi (1837–1902).

5. False positive test for syphilis in SLE by Reinhart and Hauck (1909);

6. Endocarditis lesions in SLE by Libman and Sacks in New York (1923);

7. Glomerular changes by Baehr (1935),

8. ‘Diff use connective tissue disease’ by Klemperer, Pollack and Baehr (1941).

9. The ‘LE’ cell by Hargraves, Richmond and Morton at the Mayo Clinic in 1948.

DEFINITIONInflammatory autoimmune disorder affecting multiple organ systems characterized by the production of autoantibodies directed against cell nuclei”

Natural History and Course

Etiology

Genetic (HLA DR3 association)Abnormal immune response

EnvironmentalUVHormones (Estrogen, Prolactin)Demethylating drugs (Biologic, antiviral..) Infectious Endogenous viruses or viral-like elements

EPIDEMIOLOGYPrevalence influenced by age, gender, race, and geneticsPrevalence: 1:2000Peak incidence 16-55 years (Tripled last 40 yrs)Black > White (4:1)Urban > Rural Female predominance 9:1HLA DR3 association, Family History

Severity is equal in male and female

PATHOPHYSIOLOGYIncreased amounts of apoptosis-related endogenous nucleic acids stimulate the production of IFNα and promote autoimmunity by breaking self-tolerance through activation of antigen-presenting cells.

Once initiated, immune reactants such as immune complexes amplify and sustain the inflammatory response.

Pathogenesis

Lupus criteria

For the purpose of identifying patients in clinical studies, a person has SLE if 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation. It is important to remember that a patient may have SLE and not have 4 criteria.

CLINICAL FEATURES: Mucocutaneous

Malar Rash (butterfly erythema) Discoid rash Photosensitive rash Subacute cutaneous LE Livedo reticularis Alopecia Raynaud’s

Vasculitic ulceration

Oral ulceration

Nasal septal perforation

Nailfold capillary changes

Lupus criteria (pneumonic)

M D S O A P B R A I N

Lupus criteria (pneumonic)

Malar rash

Discoid lupus

Serositis

Oral ulcers

Arthritis

Photosensitivity

Blood abnormalities

Renal

ANA

Immune

Neurologic

Malarrash

M

D

S

O

A

P

Malarrash

Discoidrash

M

D

S

O

A

P

Discoidrash

Discoidrash

Vasculitis

Alopecia

Lupus criteria (pneumonic)

Serositis

Pleuritis, pleural effusion

Pericarditis, pericardial effusion

Ascites

M

D

S

O

A

P

Oral ulcers

M

D

S

O

A

P

Arthritis (with swelling)

M

D

S

O

A

P

Arthritis (Jaccoud’s)

PhotosensitivityM

D

S

O

A

P

Blood abnormalities

Leukocytopenia (< 4000 on 2 + occasions)

Lymphopenia (< 1500 on 2 + occasions)

Hemolytic anemia

Thrombocytopenia (<100, 000)

B

R

A

I

N

B

R

A

I

N

Renal: A) Proteinuria (>500 mg/24hrs) B) Cellular casts

Pathogenesis

Immune aggregates are present at sites of injury in glomeruli, and in the tubules also in about two-thirds of renal biopsies, as are complement components.

Whether these are derived from circulating complexes or from in situ combination of antigen and antibody is still unclear.

Pathogenesis

The effector mechanisms of renal damage (complement, polymorphs, monocytes, cytokines, eicosanoids, etc.) are similar in lupus and primary glomerulonephritis, but the interstitial cellular infiltrates in lupus often show an excess of CD8+ cytotoxic T lymphocytes over CD4+

Renal Manifestations of Lupus

Anti-nuclear antibodies (ANA)

Rim

Nucleolar

Diffuse

Speckled

B

R

A

I

N

Immune abnormalities

Smith antibody

Anti-ds DNA antibody

Anti-phospholipid antibody (1997 modification)

Anti-cardiolipin antibody (IgG or IgM)Biologic false positive VDRL (> 6 months)Lupus anticoagulant

B

R

A

I

N

Neurologic: A) Seizure B) PsychosisB

R

A

I

N

Extrarenal Manifestations

Constitutional

Musculoskeletal 80%

Mucocutaneous 33%

Serositis

Hematological

Neuro-psychiatric System 30-45%

Lung 75%

Secondary Antiphospholipid Antibody Syndrome

Ocular

Cardiac

Gastrointestinal

Laboratory Investigations

Antinuclear Antibodies

Hematology

Antiphospholipid Antibodies

Compliments C3 – C4

ESR, CRP

Antinuclear Antibodies

Differential diagnosis

Rheumatic fever

Rheumatoid arthritis

Hemolytic anemia

Mixed connective tissue disease (MCTD)

Henoch-Scho¨nlein purpura (HSP)

IgA Nephropathy

Diagnosis

High index of suspicion

Immunologic Tests Crithedia lucilae kinetoplast test

Hypocomplementemia

Abnormal urine and/or

Reduced renal function

Renal Histologic Findings

Glomerular Appearances

Mesangial type lupus nephritis,WHO class II.

WHO class IV lupus nephritis.

Outcome and Mortality

Treatment of Lupus Nephritis

The Acute Phase: Induction Treatment

Corticosteroids.

Cytotoxic Agents.

Plasma Exchange.

Rituximab (Humanized monoclonal antibody)

IV Cyclophosphamide For Lupus Nephritis

Pulsed intravenous cyclophosphamide therapy in conjunction with low dose prednisone Seven (7) total doses of monthly i.v. cyclophosphamide beginning with 500 mg/m2 body surface area and increasing to 750 and then 1000 mg/m2 as tolerated. Good clinical response - Patient begins every 3 month cyclophosphamide until a total of 36 months have elapsed.

Inclusion Criteria

1. Decline in creatinine clearance < 75 ml/min/1.73m2 OR

2. Renal biopsy evidence of active disease- as determined by WHO classification (levels III, IV, V, or VI) OR

3. If failing' to improve in renal function after 6 months of high dose prednisolone

Clinical Manifestations

Pre Post

% %

Constitutional 86 18

Mucocutanous rash 68 36

Alopecia 50 4.5

Arthralgia/arthritis 81.8 31.8

Raynaud’s phe. 4.5 0

Pericardial effusion 27 4.5

Lymphadenopathy 31.8 0

Hematological 63.6 27

Neuropsychiatric 13.6 9

Hematuria 54.5 31.8

Proteinuria 90.9 50

NS 63.6 31.8

Hypertension 31.8 31.8

Renal insufficiency 9 9

Chemical Pre Post         

Normal

BUN 17.4 13.95 <18

Cr 0.8 0.7 <1

WBC 5.45 6.05 4-10.5

Hct 29.95 36.09 36-48

Plts 257.46 283.55 140-440

CRP 3.68 1.86 <0.8

ESR 71.06 29.6 1-20

C3 50.27 92.92 >85

C4 7.7 14.015 >14

dsDNA 973.6 468.96 <25

U-Protein 1329.7 752.8 10-150

Creatinine Clearanc 107.86 122.6 >80

Renal biopsies pre & post Tx

Biopsy Pre Post WHO Class

5 9.5% 63.6%4 66.7% 0%3 0% 36.4%2 0% 18.2%

 Activity

Severe 42.8% 0%Moderate 71.4% 0%Mild 28.6% 37.5%No 0% 62.5%

 Chronicity

Severe 0% 0%Moderate 0% 0%Mild 28.6% 44.4%No 71.4% 55.5%

The Chronic Phase: Maintenance Treatment

Corticosteroids.Cytotoxic Agents.Cyclosporine.Intravenous Gamma Globulin.Total lymphoid irradiationNonsteroidal anti-inflammatoryThromboxane synthetase inhibitorsFish Oil and Dietary Fat

When Can We Stop Treatment in Lupus Nephritis?

Goal: suppression of disease with minimum side effects

Repeat renal biopsies

Stable renal function,

Lack of proteinuria, and normal immunologic tests are signs of success.