Systemic Lupus Erythematosus

1. Systemic Lupus Erythematosus (SLE)

2. OUTLINE • Definition • Epidemiology • Pathophysiology • Clinical features • Classification and diagnosis • Treatment • Prognosis • Lupus related syndromes APS??

3. Definition • 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.

4. Epidemiology Prevalence influenced by age, gender, race, and geographical area • Prevalence=30-50/100000 • Peak incidence 15-45 years • Female predominance-F:M=9:1 Can occur in childhood or later in life

5. Etiology

6. 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

7. Pathophysiology

8. Abnormal immune system • 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.

9. 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.

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

13. General simptoms: • Fever • Fatigue • Weight loss • Malaise = generally feeling ill • Anorexia

14. Clinical features: • Cutaneous manifestations: • LE-specific lesions can be classified into acute, subacute, and chronic. • LE-non specific lesions:alopecia, urticarial lesions, vasculiticlesions, sclerodactyly, livedoreticularis, 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.

15. Immunological findings • ANA - 95-100%-sensitive but not specific for SLE • Anti -ds DNA-specific(60%)-specificfor 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

16. Classification and diagnosis 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

17. 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

18. 1.Malar rash=fixed erithema,flat or raised over the malar eminences, tending to spare the nasolabial folds (“butterfly rash”)

19. Butterfly rash

20. 2.Discoid rush=erythematous raised patches with adherent keratotic scaling and follicular plugging;atrophic scarring may ocur in older lesions

21. 3.Photosensitivity=skin rash as a result of unusual reaction to sunlight, by patient history or physician observation 4.oral ulcers=oral or nasopharyngeal ulceration,usually painless,observed by a physician

22. 5.arthritis=nonerosive arthritis involving two or more peripheral joints, characterized bt tenderness, swelling or effusion (RX: no erosions, periarticular osteopenia + soft tissue swelling) Jaccoud’s Arthopathy: Nonerosive, ReducebleDeformities

23. 6.serositis-pleuritis=convincing history of pleuritic pain or rub heard by physician or evidence of pleural effusion or -pericarditis documented by EKG or rub or evidence of pericardial effusion 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

24. 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

25. Clinical diagnosis?!? • 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

26. Monitoring the lupus pacients SLE disease activity index (SLEDAI) Clinical featurescore • 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

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

28. Complications 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.

29. Treatment SLE • 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).

30. 2.Drug theraphy • NSAIDs • Antimalarials • Glucocorticoids • immunosuppressive agents : -azathioprine 1-2 mg/kg/day -mycophenolate mofetil 500-1500mg/day -methotrexate: 20 mg/week • Cyclosporine • Intravenous immunoglobulin therapy • Rituximab ?!? • Belimumab

31. NSAIDs • 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

32. Antimalarials • 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 200-400 mg/day

33. Corticosteroids • 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.

34. Immunosupresive drogs • 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

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

37. Antiphospholipid Antibody Syndrome (APS) • 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

38. APS Classification criteria 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: • False-positive test for syphilis?!??? • Lupus anticoagulant • Anticardiolipin • Anti beta2 glycoprotein 1 APS is present if at least one of the clinical criteria and one of the laboratory criteria are met.

39. Treatment APS • Anticoagulation with warfarin (teratogenic) • subcutaneous heparin and aspirin is usual approach in pregnancy

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