(SLE)

 Definition  Epidemiology  Pathophysiology  Clinical features  Classification and diagnosis  Treatment  Prognosis  Lupus related syndromes APS??

 Inflammatory autoimmune disorder affecting multiple organ systems characterized by the production of autoantibodies  Typically the course of the disease is a series of remissions and exacerbations.  Virtually any organ of the body may be involved, but most often harms the heart, joints, skin, lungs, blood vessels, liver, kidneys, and nervous system.heart jointsskinlungsblood vesselsliver kidneysnervous system

Prevalence influenced by age, gender, race, and geographical area ◦ Prevalence=30-50/ ◦ Peak incidence years ◦ Female predominance-F:M=9:1 Can occur in childhood or later in life

Immunologic anomalies Genetic predisposition Enviromental factors Hormonal factors

 Genetic predisposition: HLA DR and DQ and non HLA  Enviromental factors:  Ultraviolet light (especially UVB)  Smoking  Viral infections: Ebstein Baar virus  Silica and mercury exposure  Drugs  Extreme stress  Hormonal factors (female predominance): estrogen

 Sustained presence of autoantigens: increased apoptosis, impaired clearance of apoptosis  Hyperactivity in B and T lymphocyte.  Increased expression of surface molecules participating in cell activation in both B- and T-cell.  Overproduction of IL-6 and IL-10  Defective regulatory mechanism.

 Autoantibodies to DNA, RNA, and a host of other cell nucleus antigens.  Circulating immune complexes are frequently observed and these may deposit in the kidney, skin, brain, lung, and other tissues. It causes inflammation and tissue damage by a number of mechanism, notably fixation and activation of the complement system.

Skin cell T cell B cell APC Defective IC clearance UV light External AgSelf Ag Ab IC Target Genetic susceptibility

 Fever  Fatigue  Weight loss  Malaise = generally feeling ill  Anorexia

 Cutaneous manifestations:  LE-specific lesions can be classified into acute, subacute, and chronic.  LE-non specific lesions:alopecia, urticarial lesions, vasculitic lesions, sclerodactyly, livedo reticularis, Raynaud phenomenon.  Musculoskeletal: arthritis, myositis, osteonecrosis.  Cardiopulmonary involvement: pleurisy, pericarditis, Libman-Sacks endocarditis, pulmonary hypertension, interstitial pneumonitis, coronary artery disease.  Renal manifestations: lupus nephritis (nephrotic syndrome in progresion to renal insufficiency and failure-renal biopsy  VI classes of lupus nephritis. Histologic classification by renal biopsy is useful to plan therapy ), lupus cystitis.  Neuropsychiatric manifestations: psychosis, seizures, encephalopathy, coma, stoke, meningitis, peripheral neuropathy.  Gastrointestinal involvement: esophageal dysmotility, hepatomegaly, splenomegaly, mesenteric vasculitis.  Ocular features: secondary Sjogren syndrome, slcleritis, retinitis, uveitis.

 ANA %-sensitive but not specific for SLE  Anti -ds DNA-specific(60%)-specific for SLE, but positive to other non lupus conditions  4 RNA associated antibodies ◦ Anti-Sm (Smith)-high dagnostic specifity for SLE ◦ Anti Ro/SSA-antibody ◦ Anti La/SSB-antibody ◦ Anti-RNP  Antiphospholipid antibody ◦ Biologic false + RPR ◦ Lupus anticoagulant (antibodies to coagulation factors; risk factor for venous and arterial thrombosis and miscarriage. Prolonged aPTT) ◦ Anti-cardiolipin  Depressed serum complement  Anti hystones antibodies

American College of Rheumatology 4/11 criteria=diagnosis SLE “SOAP BRAIN MD”  Serositis – heart, lung, peritoneum  Oral ulcers – painless esp palate  Arthritis – non-erosive  Photosensitivity

 Blood disorders - ↓RBC (Coombs +), PLT, WCC, Lymphocytes  Renal involvement  ANA titer  Immunologic phenomena – anti-dsDNA Ab, anti- Sm Ab, antiphospholipid Ab, false WR +  Neurological disorders  Malar rash  Discoid rash

4.oral ulcers=oral or nasopharyngeal ulceration,usually painless,observed by a physician

Jaccoud’s Arthopathy: Nonerosive, Reduceble Deformities

7.renal disorder-proteinuria>0.5 g/day or >3+ dipstick proteinuria or cellular casts 8.neurologic disorder=seizures or psychosis in the absente of offending drugs or known metabolic derangements 9.hematologic disorder: -hemolytic uremia or -leukopenia <4000/mm3 on two or more occasions or -lymphopenia<1500/mm3 on two or more occasions or -thrombocytopenia<100,000/mm3 in the absence of offending drugs

10.immunologic disorders: Antibody to native DNA Antibody to Sm Positive test for antiphospholipid antibodies including -abnormal Ig G or IgM anticardiolipin -lupus anticoagulant -fals-positive serologic test for syphilis (WR) 11.Positive antinuclear antibodies (ANA) in the absence of drugs known to be associated with drug-induced lupus

 Must have 4 of 11 for Classification ◦ Sensitivity 96% ◦ Specificity 96%  Like RA, diagnosis is ultimately clinical  Not all “Lupus” is SLE ◦ Discoid Lupus ◦ Overlap syndrome ◦ Drug induced lupus ◦ Subacute Cutaneous Lupus

SLE disease activity index (SLEDAI) Clinical feature score  seizure, psychosis, organ brain syndrome 8  visual disturbance, cranial nerve disorder 8  lupus headache, cerebrovascular accidents, 8  vasculitis 8  arthritis 4  myositis 4  urinary casts, hematuria, proteinure, pyuria 4  rash, alopecia, mucosal ulcers, 2  pleurisy, pericarditis 2  low complement, increased DNA binding 2  fever 1  thrombocytopenia, leucopenia 1

 Drug-induced lupus  Other connective tissue diseases: RA, dermatomyositis, overlap syndrome  Fibromyalgia  Some Viral infections: parvovirus, HIV,hepatitis B or C  Malignancy

1. SLE complications:  Renal failure occurs in lupus nephritis  Strokes can occur from active central nervous system lupus 2. Glucocorticoid complications:  Cataracts  Osteoporotic fractures  Osteonecrosis  Diabetes mellitus  Infections  Cushingoid habitus  Weight gain  Acne franck depression 3.Opportunistic infections: until proved otherwise,consider infection in a pacient with SLE who is febrile 4. Malignancy.

 Treatment plans are based on patient age, sex, health, symptoms, and lifestyle  Goals of treatment are to: -prevent flares -treat flares when they occur -minimize organ damage and complications 1.Lifestyle changes  avoiding direct sunlight, covering up with sun-protective clothing, and using strong UVA/UVB sunblock lotion can also be effective in preventing photosensitivity problems.  weight loss is also recommended in overweight and obese patients to alleviate some of the effects of the disease, especially where joint involvement is significant  avoiding infections,extreme stress or fatigue  Avoiding drugs lupus-like effect (procainamide, hydralazine,methyldopaisoniazid).

 NSAIDs  Antimalarials  Glucocorticoids  immunosuppressive agents : -azathioprine 1-2 mg/kg/day -mycophenolate mofetil mg/day -methotrexate: 20 mg/week  Cyclosporine  Intravenous immunoglobulin therapy  Rituximab ?!?  Belimumab

 NSAIDs have been used with success for the management of SLE manifestations such as fatigue, constitutional symptoms, musculoskeletal complaints, and serositis.  In contrast to antimalarial drugs there is no evidence that NSAIDs  reduce the risk of flare nor is there a rationale for administering them  chronically in the absence of symptoms  Adverse effects of NSAIDs: renal insufficiency resulting  from decreased glomerular filtration, impairment of blood flow, and, occasionally, interstitial nephritis; hepatitis; fluid retention; hypertension and development of gastric and duodenal

 The antimalarial drugs (hydroxychloroquine, chloroquine, and quinacrine) are the mainstay of management for mild to moderately severe lupus and are also indicated as adjunctive therapy of severe lupus and to prevent flares.  The major complication: ocular toxicity!!  These drugs appear to have several favorable effects on thrombotic and cardiovascular risk. Plaquenil mg/day

 Corticosteroids are the mainstay of initial treatment of active lupus requiring prompt treatment.  Corticosteroids rapidly suppress the majority of inflammatory disease manifestations if given in sufficient quantity  Improvement is generally more rapid than the response to immunosuppressive or antimalarial drugs.

 Mild cases (mild skin or joint involvement): NSAID, local treatment, hydroxy-chloroquin  Cases of intermediate severity (serositis, cytopenia, marked skin or joint involvement): corticosteroid (12-64 mg methylprednisolon), azathioprin, methotrexat  Severe, life-threatening organ involvements (carditis, nephritis, systemic vasculitis, cerebral manifestations): high-dose intravenous corticosteroid + iv. cyclophosphamide + in some cases: plasmapheresis or iv. immunoglobulin, or, instead of cyclophosphamide: mycophenolate mofetil  Some cases of nephritis (especially membranous), myositis, thrombocytopenia: cyclosporine

 Unpredictable course  10 year survival rates exceed 85%  Most SLE patients die from infection, probably related to therapy which suppresses immune system

 APS is an autoimmune multisystemic disorder of recurrent thrombosis and/or pregnancy losses that is associated with the presence of antiphospholipid (aPL) antibodies.  50% of pacients with SLE have APS.  Clinical findings: Cutaneous: livedo reticularis, superficial thrombophlebitis, leg ulcers Cardiopulmonary: pulmonary emboli and pulmonary infarcts, miocardial infarctation, Libman Scks endocarditis. Gastrointestinal:hepatic or splenic infarcts, Budd-Chiari syndrome Neurologic: Transient ischemic attacks or strokes Endocrinologic: adrenal insufficiency Reproductive:pregnancy losses, preeclampsia,HELLP syndrome. Optic neuropathy

Vascular thrombosis-arterial,venous or small vessel OR Pregnancy morbidity  One or more fetal deaths  One or more premature births due to severe preeclampsia or placental insufficiency  Three or more first trimester losses PLUS one of laboratory criteria: 1. False-positive test for syphilis?!??? 2. Lupus anticoagulant 3. Anticardiolipin 4. Anti beta2 glycoprotein 1 APS is present if at least one of the clinical criteria and one of the laboratory criteria are met.

◦ Anticoagulation with warfarin (teratogenic) ◦ subcutaneous heparin and aspirin is usual approach in pregnancy