Systemic Lupus Erythematosus

Systemic Lupus Erythematosus

Definiton and Prevalence Autoimmune disease Organs and cells damage Tissue-binding autoantibodies and immune complexes 90% women of child-bearing years 15-50 cases/100,000

Pathogenesis and Etiology Susceptibility genes - environment interactions abnormal immune responses pathogenic autoantibodies+immune complexes deposit in tissue activate complement inflammation irreversible organ damage Multigenic disease: HLA-D2,3,8 Region on chromosome 16 contains genes that predispose Female sex Estrogen-containing oral contraceptives

Pathogenesis and Etiology2 Environmental factors: exposure to ultraviolet light, EBV can trigger Geneticsusceptibility+environment+sex abnormal immune responses autoimmunity

Pathology Renal biopsy pattern and severity of injury diagnosis best therapy Class III, IV, V disease aggressive immunosuppression Class I, II,VI no treatment Leukocytoclastic vasculitis in SLE

Classification of Lupus Nephritis (LN) Class I: Minimal Mesangial LN Class II: Mesangial Proliferative LN Class III: Focal LN Class IV: Diffuse LN Class V: Membranous LN Class VI: Advanced Sclerotic LN

Diagnostic criteria for SLE 1. Malar rash: fixed erythema, flat or raised, over the malar eminences 2. Discoid rash: erythematous circular raised patches with adherent keratotic scaling and follicular plugging 3. Photosensitivity: exposure to ultraviolet light causes rash 4.Oral ulcers: includes oral and nasopharyngeal ulcers, observed by physician

Diagnostic criteria for SLE 2. 5. Arthritis: nonerosive arthritis of two or more peripheral joints, with tenderness, swelling, or effusion 6. Serositis: pleuritis or pericarditis documented by ECG or rub or evidence of effusion 7. Renal disorder: proteinuria > 0,5 g/d or 3+, or cellular casts

Diagnostic criteria for SLE 3. 8. Neurologic disorder: seizures or psychosis without other causes 9. Hematologic disorder: hemolytic anemia or leukopenia (<4000/μL) or lymphopenia (<1500/μL) or thrombocytopenia (<100,000/μL) in the absence of offending drugs 10. Immunological disorder: anti-dsdna, anti-sm, and/or anti-phospholipid

Diagnostic criteria for SLE 4. 11. Antinuclear antibodies: an abnormal titer of ANA by immunofluorescence or an equivalent assayat any point in time in the absence od drugs known toinduce ANAs If 4 of these 11 criteria, well documented, are present at any time in a patient s history, the diagnosis is likely to be SLE.

Autoantibodies in SLE ANA (Antinuclear antibodies): prevalence 98%, best screening test, repeated negative tests make SLE unlikely Anti-dsDNA: prevalence 70%, high titers are SLE-specific, and is some patients correlate with disease ctivity, nephritis, vasculitis Anti-Sm: prevalence 25%,, specific for SLE, no definite clinical correlations

Autoantibodies in SLE 2. Anti-RNP: prevalence 40%, not specific for SLE, high titers associated with overlap syndromes Anti-Ro (SS-A): prevalence 30%, not specific for SLE, associated with sicca syndrome, subacute cutaneous lupus, and neonatal lupus with congenital heart block Anti-La (SS-B): prevalence 10%,

Autoantibodies in SLE 3. Antihistone: prevalence 70%, more frequent in drug-induced SLE Antiphospholipid: prevalence 50%, predisposes to clotting, fetal loss, thrombocytopenia Antineuronal (includes anti.glutamate receptor): prevalence 60%, correlates with active CNS lupus Antiribosomal P: prevalence 20%, correlates with depression or psychosis due to CNS lupus

Diagnosis of SLE Characteristic clinical features + autoantibodies The presence of multiple autoantibodies without clinical symptoms no SLE Establish the severity and potential reversibility of SLE

Systemic manifestations Fever Weight loss Anemia Fatigue Myalgia/arthralgias

Musculoskeletal manifestations Polyarthritis: hands, fingers, wrists, knees Erosions on joint x-rays: rare Myalgias without frank myositis Steroid theapy muscle weakness

Cutaneous manifestations DLE: discoid lupus erythematosus Systemic rash SCLE: subacute cutaneous lupus erythematosus Circular discoid lesions on the face and scalp Rash photosensitive on the face cheeks and nose butterfly rash,chin, V region of the neck, upper back

Renal manifestations Lupus nephritis Urinalysis: microscopic hematuria, proteinuria >500 mg/24 h Nephrotic syndrome Secondary hypertension Accelerated atherosclerosis

Nervous system manifstations Headaches Seizures Psychosis Myelopathy

Vascular occlusions Antiphospholipid Ab-s Acute thrombotic events Brain vasculitis Accelerated atherosclerosis AMI

Pulmonary manifestations Pleuritis Pleural effusion Pulmonary infiltrates on imaging Interstitial inflammation fibrosis Intraalveolar hemorrhage

Cardiac manifestations Pericarditis tamponade Myocarditis Fibrinous endocarditis of Libman- Sacks embolic events, mitral/aortic valvular insufficiencies Increased risk for AMI

Hematologic manifestations Anemia Hemolysis Leucopenia Lymphopenia Thrombocytopenia

Gastrointestinal manifestations Nausea, vomiting Diarrhea Diffuse abdominal pain autoimmune peritonitis, intestinal vasculitis Active SLE AST ALT

Ocular manifestations Sicca syndrome= Sjögren s syndrome Nonspecific conjunctivitis Retinal vasculitis Optic neuritis blindeness Steroids cataracts, glaucoma

Laboratory tests Establish the diagnosis Rule out the diagnosis Follow the course of disease Identify adverse effects of therapies

Tests for autoantibodies ANA ANA-negative lupus Anti-dsDNA Anti-Sm antibodies ACLA (anticardiolipin antibodies) APS (antiphospholipid antibody syndrome)

Tests for following disease course Anti-dsDNA C3 complement

Treatment of SLE No cure for SLE Control acute, severe flares Maintenance therapy suppress symptoms: 5 to 10 mg Prednisone per day Prevention of organ damage

Treatment of SLE 2. Glucocorticoids/steroids: oral Prednisone 0,5-1 mg/kg/day for severe disease Methylprednisolone: iv. lupus nephritis 1000 mg iv. for 3 days Cyclophosphamide: iv. 7-25 mg/kg/month x6 or oral 1.5-3 mg/kg/day Azathioprine: oral 2-3 mg/kg/day

Treatment of SLE 3. Hydroxychloroquine: oral 200-400 mg/day Mycophenolate mofetil: oral 2-3 g/day Methotrexate: oral 10-25 mg once week Topical glucocorticoids NSAIDs

Life-threatening SLE: Proliferative forms of lupus nephritis 1000 mg Methylprednisolone iv. daily for 3 days response begin 24 h Cyclophosphamide iv. 500-750 mg/m 2 monthly for 3-6 months, then Azathioprine or Mycophenolate mofetil Responses begin -16 weeks after treatment Mycophenolate mofetil Cyclosporine: oral 3-5 mg/kg/day

Lupus and Antiphospholipid Antibody Syndrome Venous or arterial clotting Repeated fetal loss 2 positive est for antiphospholipids Therapy: long-term anticoagulation INR 2-3 recommended

Patients outcomes, prognosis, and survival Survival: 95% at 5 years, 90% at 10 years, 78% at 20 years

Drug-induced lupus Procainamide Propafenone Hydralazine ACE-inhibitors (Enalapril) Beta blockers Propylthiouracil Chlorpromazine Lithium Carbamazepine, Phenytoin Isoniazid Sulfasalazine Simvastatin, Lovastatin Interferons, TNF inhibitors

Sjögren s syndrome Definition: chronic, slowly progressive autoimmune disease Lymphocytic infiltration of the exocrine glands xerostomia and dry eyes Malignant lymphoma Primary and secondary forms Middle-aged women Prevalence: 0.5-1 %

Pathogenesis T cell lymphocytic infiltration of the exocrine glands salivary gland enlargement B lymphocyte hyperreactivity Monoclonal immunoglobulins Anti-Ro/SS-A,anti-La/SS-B Abs Antibodies to α-fodrin (salivary glandspecific protein)

Clinical manifestations Diminished lacrimal and salivary gland function Mucosal dryness = xerostomia Difficulty in swallowing dry food Pnrease in dental caries, problems in wearing complete dentures Dry, sticky oral mucosa Saliva from the major glands not expressible Enlargement of the parotid

Clinical manifestations 2. Diagnotic tests: sialography, scintigraphy, sialometry Labial minor salivary gland biosy focal lymphocytic infiltrates Keratoconjunctivitis sicca Measurement of tear flow by Schirmer s test Decrease in mucous gland secretion of the upper and lower respiratory tree Atrophic gastritis Dy skin and external genitalia

Extraglandular manifestations Arthralgias/arthritis Raynaud s phenomenon Lympadenopathy Lung involvement Vasculitis Kidney involvement interstitial nephritis Liver involvement Lymphoma Anemia, ESR

Diagnosis 1. Ocular symptoms: dry eyes, use of arteficial tear 2. Oral symptoms: dry mouth, swollen salivary glands, frequent liquid drinking 3. Ocular signs: positive Shirmer s test 4. Histopathology: in minor salivary glands focal lymphocytic sialodenitis

Diagnosis 2. 5. Objective evidence of salivary gland involvement: parotid sialography, salivary scintigraphy, decreased salivary flow (<1.5 ml in 15 min) 6. Antibodies in the serum to Ro/SS-A or La/SS-B antigens, or both Dg: any 4 of the 6 items, or any 3 of the 4 objective criteria items

Treatment Symptomatic relief Arteficial tears: Liquifilm, 0.5% Methylcellulose, Hypo Tears Antidepressants, diuretics should be avoided decrease salivary and lacrimal secretion Xerostomia: fluid Pilocarpine 5mg 3x daily stimulate secretions