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 Malar Rash Discoid Rash Photo- sensitivity Rash Nonerosive Arthritis Pleurisy Pericarditi s Pleurisy Pericarditi s Renal Disorder (Lupus Nephritis) Renal Disorder (Lupus Nephritis) Seizures or Psychosis Leuko- penia Hemolytic anemia Thrombo- cytopenia Leuko- penia Hemolytic anemia Thrombo- cytopenia Anti- nuclear Antibody (ANA) dsDNA APL 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

VirusCancer Cell Dying Cell 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 Lymphocyte Target Dying Cell

Killer Antibodies The 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 Antibodies The 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

ProblemGene Too many dying cellsTNF, PARP White cells too active or long-lived Il-10, IL4, IFN , and their receptors Antibodies too abundant or sticky HLA class 1 Immunoglobulin chains Too little complementC1Q, C2, C4 Inadequate transportFc receptors Complement 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 FlareChronic ActivityRemission 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 FlareChronic ActivityRemission 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 Immune Dysfunction Genetic susceptibility Gender Environmental factors o UV light o Infection Genetic susceptibility Gender Environmental factors o UV light o Infection Defective Regulatory Circuits Defective Regulatory Circuits Defective Immune Complex Clearance Defective Immune Complex 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?