Sytemic Lupus Erythematosis

The New Understanding: Complexity and Promise

Jan L Hillson MD

Gold standard is agreement among specialists

To create the ACR criteria Several specialists made lists of all the features

seen in the patients they say have SLE These lists were compared A core set was selected

Systemic Lupus - Definition

ACR Criteria for Lupus Diagnosis

• Malar Rash

• Discoid Rash

• Photo-sensitivity Rash

NonerosiveArthritis

PleurisyPericarditi

s

Renal Disorder(Lupus

Nephritis)

Seizures or Psychosis

• Leuko-penia

• Hemolytic anemia• Thrombo-

cytopenia

• Anti- nuclear Antibody (ANA)

• dsDNA• APL

Oral Ulcers

SKIN GI MUSCULO-SKELETAL

PULMONARY /CARDIAC RENAL NEUROLOGICAL HEMATOLOGIC IMMUNOLOGIC

Four at any time possible SLE DIAGNOSIS

Fatigue Rash Joint paint Pleurisy, pericarditis

Kidney disease Abnormal clotting Inflamed blood vessels Reduced blood cells

ACR Criteria Define a Heterogeneous Group of Disorders, Prevalence ~1/1000

Virus CancerCell

DyingCell

Normal Immune System Function: Recognition, Activation, Clearance, Reset

Cells of the immune system recognize the target, bind to it, become activated, and make antibodies against the target.

Target

Lymphocytes

When the target is a dying cell, the antibodies are autoantibodies

ANA DsDNA RO LA Anti-Smith Anti-RNP

LymphocyteTargetDying Cell

Killer

AntibodiesThe antibodies bind the target and complement.

Complement binds to transport cells, which clear the immune complex.

Dying Cell

Autoantibodies ANA Anti-DsDNA Anti-Smith Anti-RNP Ro/La

Killer

AntibodiesThe antibodies bind complement.

Complement binds to transport cells, which clear the immune complex.

Dying Cell

Autoantibodies ANA Anti-DsDNA Anti-Smith Anti-RNP Ro/La

Killer

The virus, dead cell, or cancer cell is cleared.

The immune system resets to a resting state, but keeps the memory of how to respond

Killer

If the immune system does not reset perfectly, immune cells may damage normal cells, and antibodies may bind to healthy tissue.

Dysregulation of the normal process of recognition, activation, clearance, and reset of the immune system

Leading to persistence of pathogenic (damaging) subsets of immune cells and proteins

SLE: Cause

Problem GeneToo many dying cells TNF, PARP

White cells too active or long-lived

Il-10, IL4, IFNg, and their receptors

Antibodies too abundant or sticky

HLA class 1Immunoglobulin chains

Too little complement C1Q, C2, C4

Inadequate transport Fc receptorsComplement receptors

Many different genetic variations lead to persistence of self-reactive cells and Abs

Emerging Approaches: Genetics

Emerging Approaches: Expression

Systemic Lupus:Treatment

Severe / Serious Flare Chronic Activity Remission

Patient’s Condition

Patient experiences increased disease activity that threatens

organs or well-being and requires immediate aggressive treatment

Patient experiences persistent activity that is not immediately

threatening to organ systems, but requires ongoing treatment to

control symptoms

Patient experiences minimal or no disease symptoms or signs

Primary Treatment

Goal

Achieve rapid control of inflammation and disease-

mediated dysfunction

Maintain control of disease with minimal toxicity

Maintain remission with minimal toxicity

Commonly Used

Treatments

High dose corticosteroids MMF Cyclophosphamide

Low to medium dose corticosteroids

MMF / AZA / MTX Belimumab Antimalarials

Low to medium dose corticosteroids

MMF / AZA / MTX Belimumab Antimalarials

Level of Disease Activity Controlled

High

Low

SLE: Current Treatment

Severe / Serious Flare Chronic Activity Remission

Unmet Need Faster, less toxicity, Less Damage

More complete, less toxicity, safe with

pregnancy Cure

Commonly Used

Treatments

High dose corticosteroids MMF Cyclophosphamide

Low to medium dose corticosteroids

MMF / AZA / MTX Belimumab Antimalarials

Low to medium dose corticosteroids

MMF / AZA / MTX Belimumab Antimalarials

Level of Disease Activity

Controlled

High

Low

SLE: Unmet Need

Targets for Emerging Therapies

Immune Dysfunction

• Genetic susceptibility

• Gender• Environmental

factorsoUV lighto Infection

Defective Regulatory

Circuits

DefectiveImmuneComplex

Clearance

Advocate for funding for research Participate in lupus registries In consultation with your physician, consider

whether clinical trials are right for you

Understand and carefully follow your personal treatment plan

Maintain knowledge, fitness, and participation

Systemic Lupus – What Can We Do?