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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 SLE Damage SLE Activity 1 2 3 4 5 Time (years) 6 7 8 SLE Activity vs Damage Activity Nephritis Damage Renal failure/scar Inflammation and medications Osteoporosis/Fx Ovarian failure Myocardial infarction Autoantibody Determined Clinical Subsets of SLE RNP SSA (Ro) SSB (La) phospholipids Ribosomal-P ANA (+)>95% patients dsDNA ANA + > 90%, nonspecific CD40L-CD40 Interactions TCR T-cell B Cell CD3 CD40 CD40L (gp39) 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) RNP (Raynauds) Ribosomal-P (CNS, psychosis) Phospholipid (clotting and miscarriage) dsDNA (kidney disease) Pathogenesis of SLE Current Standard Therapy Mild to Moderate Disease arthritis fever pleurisy pericarditis cutaneous Therapy photoprotection NSAID corticosteroids methotrexate antimalarials topical agents physical therapy Current Standard Therapy Moderate to Severe Disease nephritis vasculitis cyclophosphamide pneumonitis CNS hematologic Therapy corticosteroids azathioprine cyclosporine IVIg plasmapheresis ??? mycophenylate mofetil Novel Therapies Immunosuppressants T cells B cells Complement Cytokine Hormonal Immunoablation Lupus Center of Excellence 2004 Lupus Center of Excellence 2003