Gender Differences in Immune Response Females resist a variety of infections better than males ??? Females may reject transplanted organs more rapidly Females have a higher frequency of autoimmune diseases

Evidence to Support Hormone Role in Human Lupus Female predominance Disease  during pregnancy, menses  Levels of androgen in women with lupus  Frequency of lupus in Klinefelter (XXY) men  Disease with estrogen administration ?

Evidence to Support Hormone Role in Murine Lupus Mouse model lupus (NZB x NZW) disease identical to human F > M Female mice die earlier than males Male castration and estrogen accelerates disease Male sex hormones delay onset of lupus in female mice

Role of Hormones on Immune Function Male hormones (androgen) suppress Female hormones (estrogen) enhance

CRITERIA FOR THE DIAGNOSIS OF SLE (As revised in 1997 by the American College of Rheumatology) A person is said to have SLE if four of these criteria are present at any time: Skin criteria Butterfly rash (lupus rash over the cheeks and nose) Discoid rash (thick rash that scars, usually on sun-exposed areas Sun sensitivity Oral ulcerations Systemic criteria Arthritis Serositis Proteinuria or cellular urinary casts Seizures or psychosis with no other explanation

Diagnostic Challenges Con 1. Interpretation of criteria 2. Manifestations not in criteria 3. Other diseases may mimick lupus 4. Evolving symptoms over time 5. Patients may present very differently

Disease Mimickers Sjogren’s syndrome Fibromyalgia (+ ANA) Early rheumatoid arthritis ITP Primary antiphospholipid syndrome Drug-induced lupus

Natural History of SLE Disease flares/activity (reversible) Organ damage (irreversible) disease treatment

Time (years) SLE Activity SLE Damage

SLE Activity vs Damage Activity Nephritis Inflammation and medications Damage Renal failure/scar Osteoporosis/Fx Ovarian failure Myocardial infarction

Autoantibody Determined Clinical Subsets of SLE RNP SSA (Ro) SSB (La) dsDNA ANA (+)>95% patients ANA + > 90%, nonspecific Ribosomal-P phospholipids

CD40L-CD40 Interactions T-cell B Cell CD40CD40L (gp39) TCR CD3 CD40: B-cells, endothelial cells, macrophages, Ag-presenting cells, renal parenchymal, tubular, etc cells CD40L: T-cells, platelets

Autoantibody Determined Clinical Subsets of SLE SSA/SSB (rash and neonatal lupus, dry eyes and mouth) dsDNA (kidney disease) Ribosomal-P (CNS, psychosis) Phospholipid (clotting and miscarriage) RNP (Raynauds)

Pathogenesis of SLE

Current Standard Therapy Mild to Moderate DiseaseTherapy arthritisphotoprotection feverNSAID pleurisycorticosteroids pericarditismethotrexate cutaneousantimalarials topical agents physical therapy

Current Standard Therapy Moderate to Severe Disease Therapy nephritiscorticosteroids vasculitis cyclophosphamide pneumonitisazathioprine CNS cyclosporine hematologicIVIg plasmapheresis ??? mycophenylate mofetil

Novel Therapies Immunosuppressants T cells B cells Complement Cytokine Hormonal Immunoablation

Lupus Center of Excellence 2004 Lupus Center of Excellence 2003