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Systemic Lupus Erythematosus

Systemic Lupus Erythematosus Definition. An inflammatory multi-system diseaseImmunologic aberrations: excessive auto-antibody production Tissue damage results from antibody and complement fixing immune complex depositionWide spectrum of clinical presentations Characterized by remissions and exacerbations.

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Systemic Lupus Erythematosus

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    1. Systemic Lupus Erythematosus ????? ?-1800 ??? ???? ??? ?????? ??? ????? ???, ??"? ???? ??????? ?? ????? ???? ??? ???. ???? ?????? ??? ?????, ??? ???????? ?? ?????.????? ?-1800 ??? ???? ??? ?????? ??? ????? ???, ??"? ???? ??????? ?? ????? ???? ??? ???. ???? ?????? ??? ?????, ??? ???????? ?? ?????.

    2. Systemic Lupus Erythematosus Definition An inflammatory multi-system disease Immunologic aberrations: excessive auto-antibody production Tissue damage results from antibody and complement fixing immune complex deposition Wide spectrum of clinical presentations Characterized by remissions and exacerbations ???? ??-??????? ?? ????? ?? ??' ?????? ?????? ??? ?? ??????? ??????, ????? ????????? ???????? ??????? ?????? ??????? ???? ?????. ???????? ???????? ???? ????? ?????? ??? ?????? ???? ??? ?????? ????? ??? ????. ????? ?? ???? ??? ?? ??????? ??????????.???? ??-??????? ?? ????? ?? ??' ?????? ?????? ??? ?? ??????? ??????, ????? ????????? ???????? ??????? ?????? ??????? ???? ?????. ???????? ???????? ???? ????? ?????? ??? ?????? ???? ??? ?????? ????? ??? ????. ????? ?? ???? ??? ?? ??????? ??????????.

    3. Epidemiology SLE - recognized worldwide Prevalence in USA: 15-50 \ 100,000 (1:2000) Incidence in USA: 1.8-7.6 \ 100,000\ year F:M 9:1 ( at age: 14-64 ) Racial predisposition: x 3 more common in blacks ????? ????? ??? ?????. ?????? 1:2,000 ????"?. ?? ??? ?? 9:1 ????-????? ???? ??????. ?? ????? ??????? ?????????? – ???? ?? ???? ????.????? ????? ??? ?????. ?????? 1:2,000 ????"?. ?? ??? ?? 9:1 ????-????? ???? ??????. ?? ????? ??????? ?????????? – ???? ?? ???? ????.

    4. Epidemiology in the young and elderly Peak incidence is at age 15-40 But: Onset may be at any age In pre-pubertal and post menopausal: female : male ratio 3:1 ??? ????? ???? 15-40, ?? ????? ?????? ??? ???. ???? ??? ???????? ?? ???? ??? ????? ???? ??? 3:1, ???? ?? ????? ???????? ?????.??? ????? ???? 15-40, ?? ????? ?????? ??? ???. ???? ??? ???????? ?? ???? ??? ????? ???? ??? 3:1, ???? ?? ????? ???????? ?????.

    5. Genetic Epidemiology SLE is a multi-genic disease In < 5% of patients a single gene is responsible Homozygous deficiencies of early components of complement (C1q, C1r, C1s, C4, C2) predispose to SLE A null allele for C4A is the HLA-linked gene most consistently associated with susceptibility to SLE ???? ???? ?????-????, ????? ?-5% ??????? ???? ???? ?? ???. ??????? ???????: ????? ???????? ??????? ?? ????? (??? ?-C4a ?????????? ??? ?????).???? ???? ?????-????, ????? ?-5% ??????? ???? ???? ?? ???. ??????? ???????: ????? ???????? ??????? ?? ????? (??? ?-C4a ?????????? ??? ?????).

    6. Genetic Epidemiology HLA class II genes are associated with production of auto-antibodies TCR genes and Ig genes may contribute to susceptibility FCgRIIA, FCgRIIIA predispose to SLE in some ethnic groups (possibly responsible for impaired IC clearing) ?? ??? ??? HLA ??????? ?????? ??????? ??????. ?? ??? ??? TCR ?-Ig ??? ??????????? ?-Fc-g-R.?? ??? ??? HLA ??????? ?????? ??????? ??????. ?? ??? ??? TCR ?-Ig ??? ??????????? ?-Fc-g-R.

    7. Q: Which of the following statements regarding genetic predisposition in SLE is incorrect? ~ 10% of SLE patients have relatives with SLE The concordance for monozygotic twins is 85% Males need more susceptibility genes Relatives of SLE patients have increased incidence of auto-antibodies 5. Relatives of SLE patients have increased incidence of other autoimmune diseases ?? ???? ????? ???? 2.?? ???? ????? ???? 2.

    8. Genetic Epidemiology concordance for monozygotic twins: 24-58% relatives of SLE patients have increased incidence of: - SLE - other auto-immune diseases - auto-antibodies ~ 10% of SLE patients have relatives with SLE males need more susceptibility genes ?????? ???????????? ?? ????? ?? 24-58%, ???? ??? ????, ?? ?? ????? ?????. ?????? ???' ?? ????? ?? ??????? ?????? ?????? ????' ????? ??????? ?????? ?-10%. ????? ?????? ????? susceptibility genes.?????? ???????????? ?? ????? ?? 24-58%, ???? ??? ????, ?? ?? ????? ?????. ?????? ???' ?? ????? ?? ??????? ?????? ?????? ????' ????? ??????? ?????? ?-10%. ????? ?????? ????? susceptibility genes.

    9. Importance of Sex hormones Female predominance (9:1) disease activity during menstrual period increased disease activity in pregnancy flares with oral contraceptive therapy abnormally rapid testosterone metabolism estrogenic metabolites persist longer ???? ????? ????? ???? ?? ??????? ??? ?????, ????? ????? ???? ???' ?????? ?????? ???????, ????? ???????? (??????). ????????? ?? ????????? ???? ???? ????? ??.???? ????? ????? ???? ?? ??????? ??? ?????, ????? ????? ???? ???' ?????? ?????? ???????, ????? ???????? (??????). ????????? ?? ????????? ???? ???? ????? ??.

    10. Environmental Factors Ultraviolet light ( UVB ) Alfalfa sprouts, chemicals ( hydrazines) ? Drugs (Resprim = Trimethoprim + sulphamethoxazole) Infections (parvovirus, CMV, HCV ) Smoking ( Discoid LE ) ???? ????? ?????? ?? ??? ???? ??? ?????? ?????. ?? ?????? ????????, ???? ?? ??????: ????? ????? UV ????? ????? ???????? ????? ???????? (?? ?? ????) – ?? ????? ?? ???????? ??? ??"? ??????? ???????????. ???? alfalfa, ????????? (hydrazines). ?????? ????????????? (resprim). ??????? ?????, ????? ???????? ??? ??? ?? ????? ????? – ????? ?????. parvo-virus ???? ????? ???????, ??? ??? ?????. ?? ?? HCV ?-CMV. ????? ???? ???????? ????? ????? (discoid LE).???? ????? ?????? ?? ??? ???? ??? ?????? ?????. ?? ?????? ????????, ???? ?? ??????: ????? ????? UV ????? ????? ???????? ????? ???????? (?? ?? ????) – ?? ????? ?? ???????? ??? ??"? ??????? ???????????. ???? alfalfa, ????????? (hydrazines). ?????? ????????????? (resprim). ??????? ?????, ????? ???????? ??? ??? ?? ????? ????? – ????? ?????. parvo-virus ???? ????? ???????, ??? ??? ?????. ?? ?? HCV ?-CMV. ????? ???? ???????? ????? ????? (discoid LE).

    11. Defective Immune Regulation B cell and T cell hyperactivity leads to: T cell dependent auto-Ab production made in high quantity Subsets of auto-Abs and the Immune Complexes they form with Ag mediate tissue damage Defective clearance of Immune Complexes Defects in immune tolerance and apoptosis Defects in T and natural killer regulatory cells ?? ????? ????? ???????? ?? ??' ??????: ????? ?????? ??? ?? ??? B ?-T ??????? ?????? ??? auto-Ab. ??????? ????? ??????? ???? ????? ??????. ?? ?? ????? ?? ?????????? ?????. ?? ???? ??????? ???????? ???????????. ?? ????? ???? T ?-NK.?? ????? ????? ???????? ?? ??' ??????: ????? ?????? ??? ?? ??? B ?-T ??????? ?????? ??? auto-Ab. ??????? ????? ??????? ???? ????? ??????. ?? ?? ????? ?? ?????????? ?????. ?? ???? ??????? ???????? ???????????. ?? ????? ???? T ?-NK.

    12. Pathogenic auto-antibodies Mechanisms of damage Direct binding to tissue via charge or cross-reactivity ( anti-DNA) Production of Immune Complexes leads to complement mediated damage Direct binding to cell membranes ( RBCs, Platelets) ????? ?? ???? ?? ????????? ?? ?? ????? ?? ???????? ????? (??? ?????????), ????? ?? ??????? ??????? ??? ???? ?"? ??????.????? ?? ???? ?? ????????? ?? ?? ????? ?? ???????? ????? (??? ?????????), ????? ?? ??????? ??????? ??? ???? ?"? ??????.

    13. Clinical Manifestations of SLE Constitutional non-specific but very common: - Fatigue - Fever - Weight Loss ???????? ??????? ?????? ?????? ????????????????? ???? ??????. ?? ?? ????????, ??? ???? ???? ????? ????? ?????? ??????? (???? ?? ????? ?? ??, ??? ???), ??? ?????? ?????. ?? ?-DD ????, ??? ?????? ?? ????? ?? ???? ?? ???????.???????? ??????? ?????? ?????? ????????????????? ???? ??????. ?? ?? ????????, ??? ???? ???? ????? ????? ?????? ??????? (???? ?? ????? ?? ??, ??? ???), ??? ?????? ?????. ?? ?-DD ????, ??? ?????? ?? ????? ?? ???? ?? ???????.

    14. Skin Manifestations LE-specific lesions Acute: - malar “butterfly rash” - generalized erythema - bullous LE Subacute cutaneous lupus Chronic lupus: - localized discoid - generalized discoid - lupus profundus ??????? ?????? Acute ????? ?????? ??? ????? ????, ????? ?????? ?????? ?? ?????? ???? ???. ????? ?????-?????? ??? ????? ????. ?? ??? ?????? ?? ????? ???. ???? ????? ????????????? ????. ?????? ??????? ???? ?? ?????????????. ????? ??????? – ???????? ??????? ?????? ????. ??????? ?????? ??? ??????? ????. Subacute ?? ?????? ???????, ?? ??? ?????: ?????????????? – ???? ?????, ?????? ????? ???? ???? (???? ?-V, ??????). ????? ???????? (??????) – ?? ??????? ?????? ????. Chronic ?????????? – ????? ????? ?? ??? ???, ????? ?????-????????? ????? ?????-????????? ????? ?? ??????? ?????. ????? ?????? ?????????, ????? ?? ???? ?? ????, ?? ??? ???? ?????. ??"? ??? ??? ???.??????? ?????? Acute ????? ?????? ??? ????? ????, ????? ?????? ?????? ?? ?????? ???? ???. ????? ?????-?????? ??? ????? ????. ?? ??? ?????? ?? ????? ???. ???? ????? ????????????? ????. ?????? ??????? ???? ?? ?????????????. ????? ??????? – ???????? ??????? ?????? ????. ??????? ?????? ??? ??????? ????. Subacute ?? ?????? ???????, ?? ??? ?????: ?????????????? – ???? ?????, ?????? ????? ???? ???? (???? ?-V, ??????). ????? ???????? (??????) – ?? ??????? ?????? ????. Chronic ?????????? – ????? ????? ?? ??? ???, ????? ?????-????????? ????? ?????-????????? ????? ?? ??????? ?????. ????? ?????? ?????????, ????? ?? ???? ?? ????, ?? ??? ???? ?????. ??"? ??? ??? ???.

    15. Butterfly- malar rash

    16. Generalized, photosensitive erythema

    17. Bullous rash

    18. Subacute cutaneous rash psoriatiform annular

    19. Discoid rash

    20. Skin Manifestations LE-nonspecific lesions Panniculitis Urticarial lesions Vasculitis Livedo reticularis Oral lesions Non-scarring alopecia ??????? ?????? ?????? ??????, ????? ???????? ????? ???????????: ?????????? – ???? ????-????? – ????? ????? ??????. ????? ???????????. ????????? – ??"? ?????? ???????, ???? ????. Livedo reticularis – ????? ????? ??????, "??? ???" ??? ?? ?? ?????? ????. ????? ???. Alopecia – ???? ???? ????? ????? ??????? ??? ?????? ??????? (??? ?? ?? ???????? ????). ??? ???? ???? ???? ???? ????????.??????? ?????? ?????? ??????, ????? ???????? ????? ???????????: ?????????? – ???? ????-????? – ????? ????? ??????. ????? ???????????. ????????? – ??"? ?????? ???????, ???? ????. Livedo reticularis – ????? ????? ??????, "??? ???" ??? ?? ?? ?????? ????. ????? ???. Alopecia – ???? ???? ????? ????? ??????? ??? ?????? ??????? (??? ?? ?? ???????? ????). ??? ???? ???? ???? ???? ????????.

    21. Panniculitis

    22. Vasculitis with finger tip ulcers

    23. Livedo reticularis

    24. Alopecia (diffuse or patchy) Non-scarring if part of SLE flare Scarring if results from discoid

    25. Skin biopsy: Lupus band test = immunofluorescent staining of IgG and complement deposits in dermo-epidermal junction ?????? ???????' – ??? ????? ???? ??? ?-dermo-epidermal junction, ?? ??????? ?? ????????? ???????? ??????? ????? ??. ??? ??? lupus band test ??? ????? ?? ?????? ????? ??, ???? ?? ????? ?? ??.?????? ???????' – ??? ????? ???? ??? ?-dermo-epidermal junction, ?? ??????? ?? ????????? ???????? ??????? ????? ??. ??? ??? lupus band test ??? ????? ?? ?????? ????? ??, ???? ?? ????? ?? ??.

    26. Skin biopsy - SLE dermatitis Thickened epidermal basement membrane (large arrows) Inflammatory infiltrates (small arrow) ??????? ??????? ????? ?-junction.??????? ??????? ????? ?-junction.

    27. Skin biopsy - Discoid lesion Hyperkeratosis (small arrow) Lymphoid infiltrates (thick arrow) Fibrosis of deep dermis ???????? ???? ????-???????, ????? ????????? ???? ?? ???????? ?????? ????? ????????.???????? ???? ????-???????, ????? ????????? ???? ?? ???????? ?????? ????? ????????.

    28. Musculoskeletal Manifestations Arthritis: - the most common manifestation of SLE - non-erosive, rarely deforming (Jaccoud’s deformity) - synovial fluid- mild inflammation - tenosynovitis-may be early manifestation Myopathy: - myositis = true inflammation - myopathy 2nd to drugs: steroids, anti-malarials ??' ??????????????? ?????? ???????? ??? ?????? ????? ????? ?????? (95% ???? ??????? ??? ???? ?-RA). ??? ?? ???????? ????? ?????? ???-???????. Jaccoud's arthrophy – ????? ????????, ???? ??? ?????????, ??? ??? ???????, ???????? ????? ????? ?? ?????? ?? ????, ?? ???????? ????? ??? ?????? ???? ?? ????. ?????? ?????. ?????? ?????????? ?? ?????, ????? ????? ????????????. ?????? ???? ????? ????? ????? ?????. ????? ??????? ????? ?????????? ?? ?????? ?????? ?????? ??????? ??????.??' ??????????????? ?????? ???????? ??? ?????? ????? ????? ?????? (95% ???? ??????? ??? ???? ?-RA). ??? ?? ???????? ????? ?????? ???-???????. Jaccoud's arthrophy – ????? ????????, ???? ??? ?????????, ??? ??? ???????, ???????? ????? ????? ?? ?????? ?? ????, ?? ???????? ????? ??? ?????? ???? ?? ????. ?????? ?????. ?????? ?????????? ?? ?????, ????? ????? ????????????. ?????? ???? ????? ????? ????? ?????. ????? ??????? ????? ?????????? ?? ?????? ?????? ?????? ??????? ??????.

    29. Jaccoud’s arthropathy

    30. Renal Disease in SLE Proteinuria: 0.5 gr\ 24 hrs ( or > +3 ) Urinary casts: RBC,granular,tubular,mixed Hematuria: > 5 RBC / high power field Pyuria: > 5 WBC / high power field prevalence: 30-65% in 3-6% renal disease is first manifestation ???? ???? ??? ?? ???? ?????? ?????? ????: ??????????? ?? ????? 0.5 ??' ?????. ?????? ???? (RBC, ??????????). ??????? ?? ????? 5 ??????' ????. ??????? ?? ????? 5 WBC ????. ?????? ?????? ?? ?????? ?????? ????? (3-6%), ?? ?? ???? (30-65%).???? ???? ??? ?? ???? ?????? ?????? ????: ??????????? ?? ????? 0.5 ??' ?????. ?????? ???? (RBC, ??????????). ??????? ?? ????? 5 ??????' ????. ??????? ?? ????? 5 WBC ????. ?????? ?????? ?? ?????? ?????? ????? (3-6%), ?? ?? ???? (30-65%).

    31. WHO Classification of Lupus Nephritis J Am Soc Nephrol 15: 241-250, 2004 Class I - Minimal mesangial LN (mesangial immune deposits seen by IF) Class II - Mesangial proliferative LN Class III- Focal proliferative LN (<50% of glomeruli with focal subendothelial immune deposits) Class IV - Diffuse proliferative segmental LN (IV-S) - Diffuse proliferative global LN (IV-G) (> 50% of glomeruli with subendothelial immune deposits) Class V - Membranous LN (global or segmental subepithelial deposits) Class VI - Advanced sclerosing LN (> 90% of glomeruli globally sclerosed) ?????????? ?? ?-WHO ?-lupus nephritis ??? ????? ???? ??? ???????? ?????: ????????? ???? ???? ??? ??????????? ????????? ????' ?????? ????. Class 1-2 – ???? ???? ???, ?? ????? ?????. Class 6 – ???????? ????????, ??? ??? ????. Class 3-5 – ???? ???? ????????. ?? ???? ???? ????? ???????. ?? ???????????? ???, ????? ????? ???? ??? ??????? ??"? ?????. ????? ??? ?????? ?????? ?????.?????????? ?? ?-WHO ?-lupus nephritis ??? ????? ???? ??? ???????? ?????: ????????? ???? ???? ??? ??????????? ????????? ????' ?????? ????. Class 1-2 – ???? ???? ???, ?? ????? ?????. Class 6 – ???????? ????????, ??? ??? ????. Class 3-5 – ???? ???? ????????. ?? ???? ???? ????? ???????. ?? ???????????? ???, ????? ????? ???? ??? ??????? ??"? ?????. ????? ??? ?????? ?????? ?????.

    32. Renal disease in SLE Mild disease - Class II Serious disease - Class III, IV, V Clinical course: - Class II: hematuria, sub-nephrotic proteinuria, preserved GFR - Class III and IV: edema, HTN nephritic sediment, mild-mod proteinuria, acute GFR - Class V: features of nephrotic syndrome, preserved/ gradual GFR 1 – ????? ????????? ????. 2 - ????? ?? ???' ?? ????????. 3-4 – ???? ???????????? ?? ????? ????????? ????-??????, ???? 3 ??????? (???? ?-50%) ?-4 ??????? (???? ?-50%). 5 – membranous, ????? ????-?????. 6 – ???????? ?? ??? ?-90% ??????????. ???? ???? ???????? ??: ?????? ?????? – ????? ???? ???? ??????????. ?????? ?????? – ?????? ???? ??? ??????.1 – ????? ????????? ????. 2 - ????? ?? ???' ?? ????????. 3-4 – ???? ???????????? ?? ????? ????????? ????-??????, ???? 3 ??????? (???? ?-50%) ?-4 ??????? (???? ?-50%). 5 – membranous, ????? ????-?????. 6 – ???????? ?? ??? ?-90% ??????????. ???? ???? ???????? ??: ?????? ?????? – ????? ???? ???? ??????????. ?????? ?????? – ?????? ???? ??? ??????.

    33. Serositis in SLE Pleuritis - occurs in 30-60% of patients Pericarditis - occurs in 20-30% Peritonitis ????? – ?? ????? ????. ???? – ????????? (60% ???????). ?????????? (20-30%). ?????????? – ???? ?? ????, ????? ?? ????? ?????.????? – ?? ????? ????. ???? – ????????? (60% ???????). ?????????? (20-30%). ?????????? – ???? ?? ????, ????? ?? ????? ?????.

    34. Cardiac Manifestations Pericarditis Myocarditis Endocarditis (Libman -Sacks endocarditis) Coronary heart disease ?? ?????????? – ??? ????. ??????????. ??????????? ?????? ??????? – ??????? ??? libmann sacks ????? ?????????. ???? ?? ????????? – ???? ????? ?????????? ???????????, ?? ???? ???????????? ????.?? ?????????? – ??? ????. ??????????. ??????????? ?????? ??????? – ??????? ??? libmann sacks ????? ?????????. ???? ?? ????????? – ???? ????? ?????????? ???????????, ?? ???? ???????????? ????.

    35. Pulmonary Manifestations Pleuritis Pneumonitis - acute or chronic Pulmonary hemorrhage - due to vasculitis Pulmonary hypertension Pulmonary embolism ????? ?? ???????? ?????? ??????: ????????? – ??? ????. ??????????? – ???? ????? ??????? ?????. ????? ????? ????? – ????????? ???? ??? ??????, ?????? ?????, ????. ??"? ?????. ????? ????? ?? ?????? ??? ???????? ???.????? ?? ???????? ?????? ??????: ????????? – ??? ????. ??????????? – ???? ????? ??????? ?????. ????? ????? ????? – ????????? ???? ??? ??????, ?????? ?????, ????. ??"? ?????. ????? ????? ?? ?????? ??? ???????? ???.

    36. Question A 40 year old woman with a 20 year history of SLE presents with: chest pain, dyspnea and fever. Current medications: Prednisone 10mg, Methotrexate 15 mg/wk, Plaquenil 400mg/d Which of the following are a possible diagnosis? 1. Pneumonia 2. Pleuritis / Pericarditis 3. Lupus pneumonitis 4. Pulmonary embolism 5. All of the above ???? ?? 40 ???? ????? ???? ?? ???????? ?? ?????. ????? ?? ????? ????, ???? ????? ????. ?????? ????????? ?-methotrexate ????? plaquenil (????? ??? ??????). DD ???? ?????. ????????? / ??????????. ?????-???????????. ????? ?????. ???? – ???? ????? ?????, ????? ??? ?? ???????????, ??? ?? ?? ?? ????? ?????. ?? ???? ????? ?? prodrome ?????? ?????? ??????? ?? ?????? – ?-DD ???? ????. ?? ?? ??????????? ???? ??? ????-???????????, ?? ?? ?????-??????????? ???? ????? ???? ?? ?????????, ?? ?? ????? ???? ????-??????????. ?????? ?????? ???? ????? CT-angio. ???? ???? (???? ?????, ??-????????), ???? ????? ????. ????? ?????? ??' ??????? ??? ????? ???? ????? ????????. ?? ???? ?????? ?????? ?? ????? ????, ????? ???? ??????-???????????.???? ?? 40 ???? ????? ???? ?? ???????? ?? ?????. ????? ?? ????? ????, ???? ????? ????. ?????? ????????? ?-methotrexate ????? plaquenil (????? ??? ??????). DD ???? ?????. ????????? / ??????????. ?????-???????????. ????? ?????. ???? – ???? ????? ?????, ????? ??? ?? ???????????, ??? ?? ?? ?? ????? ?????. ?? ???? ????? ?? prodrome ?????? ?????? ??????? ?? ?????? – ?-DD ???? ????. ?? ?? ??????????? ???? ??? ????-???????????, ?? ?? ?????-??????????? ???? ????? ???? ?? ?????????, ?? ?? ????? ???? ????-??????????. ?????? ?????? ???? ????? CT-angio. ???? ???? (???? ?????, ??-????????), ???? ????? ????. ????? ?????? ??' ??????? ??? ????? ???? ????? ????????. ?? ???? ?????? ?????? ?? ????? ????, ????? ???? ??????-???????????.

    37. Hematologic Manifestations Anemia: - in acute SLE: coomb’s positive hemolytic anemia - secondary to: chronic disease, CRF, blood loss, drugs. Leukopenia / Lymphopenia: - in active disease - secondary to drugs, infection ????????? ?? ?????? ?????? ????? ??????: ????? – ?????? ???? (?????) ????? ????? ???????? ?? coombs ?????, ??? ??????? ???? ???????. ???? ????? ?? ????? ?????? ??????, ????? ??"? ?????, ????? ?? ?? ??? ??????. ?? ?? – ?? ???? ?????? ????? ?????? (???? ????? ?? ?????). ????? ?????? ????? ??? ???????? ?? coombs ?????. ????????? ?????????? – ???? ????? ?? ???? ??????? ???????' (imuran), ?? ???? ???????, ???? ????? ????. Coombs ????? ?? ????? ???? ???????.????????? ?? ?????? ?????? ????? ??????: ????? – ?????? ???? (?????) ????? ????? ???????? ?? coombs ?????, ??? ??????? ???? ???????. ???? ????? ?? ????? ?????? ??????, ????? ??"? ?????, ????? ?? ?? ??? ??????. ?? ?? – ?? ???? ?????? ????? ?????? (???? ????? ?? ?????). ????? ?????? ????? ??? ???????? ?? coombs ?????. ????????? ?????????? – ???? ????? ?? ???? ??????? ???????' (imuran), ?? ???? ???????, ???? ????? ????. Coombs ????? ?? ????? ???? ???????.

    38. Hematologic Manifestations Thrombocytopenia: - anti-platelet abs- common, not always associated with thrombocytopenia - occurs in active SLE - may be isolated finding ( ~ 50,000 without serious bleeding ) ?????????????? – ??????? ???? ?????? ?????. ???????? ??????? ?? ?????? ?????????????. ?? ??? ????? ?? ????????????? ????? ??????? (?? ??????), ?? ??? ???? 50,000 ?????? ?? ??????.?????????????? – ??????? ???? ?????? ?????. ???????? ??????? ?? ?????? ?????????????. ?? ??? ????? ?? ????????????? ????? ??????? (?? ??????), ?? ??? ???? 50,000 ?????? ?? ??????.

    39. Neuropsychiatric SLE Central nervous system Aseptic meningitis Cerebrovascular disease Demyelinating syndrome Headache (migraine, benign intracranial pressure) Movement disorder (chorea) Myelopathy Seizure disorder Acute confusional state Anxiety disorder Cognitive dysfunction Mood disorder Psychosis Peripheral nervous system Guillain - Barre’ syndrome Autonomic disorder Mononeuropathy, single/multiplex Myasthenia Gravis Neuropathy, cranial Plexopathyy Polyneuropathy ??' ??????????????? ?? ???? ???? ???????????, ?? ?? ???? ??????? ??????????? ????????????. ??????? CNS ??????? ?-Seizure disorder – ???????? ????????? ??????. ???? ?? ???? DD ??????? ???: ????????? ?? ???????, ???? ?????? MS (??-???????????), ??? ??? ??? ???? ?????????, ???????, ??? ?????? ????, ?????? ??????????, ????, ??????, ???????, ???? ??????????????. ??????? PNS ?????????? (???? / ????), ?????? ?????? guillain barre.??' ??????????????? ?? ???? ???? ???????????, ?? ?? ???? ??????? ??????????? ????????????. ??????? CNS ??????? ?-Seizure disorder – ???????? ????????? ??????. ???? ?? ???? DD ??????? ???: ????????? ?? ???????, ???? ?????? MS (??-???????????), ??? ??? ??? ???? ?????????, ???????, ??? ?????? ????, ?????? ??????????, ????, ??????, ???????, ???? ??????????????. ??????? PNS ?????????? (???? / ????), ?????? ?????? guillain barre.

    40. Question A 35 year old woman with a 5 year history of SLE Currently on: Prednisone 40mg/d, Azathioprine 100mg/d Presents to the E.R with: Fever Acute confusional state Focal neurological findings ???? ?? 35, ?? 5 ???? ???????? ?? ?????. ?????? ????????? ????????, ????? ?? ??? ????????? ??????, ??? ?????? ????, ???.???? ?? 35, ?? 5 ???? ???????? ?? ?????. ?????? ????????? ????????, ????? ?? ??? ????????? ??????, ??? ?????? ????, ???.

    41. How would you manage her? Give her a sedative due to agitated/confused state Give her IV Antibiotics 3. Give her pulse IV Solumedrol 1000mg 4. Perform a brain CT scan and lumbar puncture 5. Give her Heparin ?? ?????? ????? ?????. ??????????? IV. ????????? (?????-????????). CT ??? ?-LP – ?? ?????? ??????. ?????.?? ?????? ????? ?????. ??????????? IV. ????????? (?????-????????). CT ??? ?-LP – ?? ?????? ??????. ?????.

    42. What does the differential diagnosis include? Infection - meningitis/ encephalitis Active CNS Lupus Toxic \ Metabolic Thromboembolic ?-DD ???? ????? ????? ???? (??? ?????? ?????), ??? ??????? ?????, ????? (??? ?????? ??????????????? ??? ????????? ?????? ?? ???????), ???? ?????-?????? ?? ????.?-DD ???? ????? ????? ???? (??? ?????? ?????), ??? ??????? ?????, ????? (??? ?????? ??????????????? ??? ????????? ?????? ?? ???????), ???? ?????-?????? ?? ????.

    43. Anti-Nuclear Antibodies (ANA) ANA : abs directed against nuclear antigens may occur in other systemic rheumatic diseases most frequent and highest in titer in SLE Positive in 98% of SLE patients detected by indirect immuno-fluorescence ?????? ????? ANA – ?????? ?????? ?? ?????. ????? ???? ???????? ???? ??????, ?? ?????? ??????, ????? ?????? ???????? ???????? ?????, ?? ????? ??? ???? ??????. ?????? ??? ?? ??? ????, ?? ???? ????? ??????????, RA. ?? ??? ??? ???? ????? ??? ??????? ???. ?? ??, ?? ???? ????? ?? ??? ??? ????? (?? ?? ??? ??? ????').?????? ????? ANA – ?????? ?????? ?? ?????. ????? ???? ???????? ???? ??????, ?? ?????? ??????, ????? ?????? ???????? ???????? ?????, ?? ????? ??? ???? ??????. ?????? ??? ?? ??? ????, ?? ???? ????? ??????????, RA. ?? ??? ??? ???? ????? ??? ??????? ???. ?? ??, ?? ???? ????? ?? ??? ??? ????? (?? ?? ??? ??? ????').

    44. Patterns of IF ANA staining Homogenous (diffuse) - dsDNA, histone SLE, drug induced SLE, RA Speckled MCTD, SLE, Sjogren, Systemic Sclerosis Nucleolar Systemic Sclerosis, Sjogren, SLE Rim (peripheral) - dsDNA histones characteristic of SLE ????? ???????? ??? ?"? ???????' ?? ???? ?????? – ?? 4 ?????? ?????: ???????, speckled, ?????????? (???? ???????? – ?? ??????????), ?????. ????? ?????? ????? ??? ?? ??????.????? ???????? ??? ?"? ???????' ?? ???? ?????? – ?? 4 ?????? ?????: ???????, speckled, ?????????? (???? ???????? – ?? ??????????), ?????. ????? ?????? ????? ??? ?? ??????.

    45. Patterns of Immuno-fluorescence ANA staining

    46. ANAs ANA’s can be divided into: those directed against dsDNA those directed against ssDNA those directed against histones those directed against non-histone nuclear proteins : nucleic acid-protein complexes ???? ??? ?????? ?-ELISA ???? ?? ??????. ?????? ANA ???? ??? ??????: dsDNA. ssDNA – ??"? ???? ??-???????. ??? ????? ????? ????????. ??? ????? ????? ??-????????? (?. ?????).???? ??? ?????? ?-ELISA ???? ?? ??????. ?????? ANA ???? ??? ??????: dsDNA. ssDNA – ??"? ???? ??-???????. ??? ????? ????? ????????. ??? ????? ????? ??-????????? (?. ?????).

    47. ANAs in SLE Autoantibody anti- ds DNA anti- ss DNA anti- Histones anti- Sm ( Smith) anti- RNP anti- Ro ( SSA) anti- La ( SSB) Prevalence 50-60% 60-70% 70% 30% 35% 30% 15% ???????? ??????? ??????: Anti-dsDNA (???? ?????????) – ?-50-60% ???????. ?????? ???? ???????, ??? ???? ???? ?"?, ?? ?? ??? ??????. Anti-smith (anti-sm) – ????? ????? ????? Smith ?-30% ???????, ???? ???? ???? ?? ?????? ???, ?? ?? ?????, ?? ?? ?? 30%. ????? anti-ssDNA (60%), anti-histone (70%), anti-Ro (SSA – 30%), anti-La (SSB - 15%), anti-RNP (35%). ?? ???? ???? ?? ?? ????????.???????? ??????? ??????: Anti-dsDNA (???? ?????????) – ?-50-60% ???????. ?????? ???? ???????, ??? ???? ???? ?"?, ?? ?? ??? ??????. Anti-smith (anti-sm) – ????? ????? ????? Smith ?-30% ???????, ???? ???? ???? ?? ?????? ???, ?? ?? ?????, ?? ?? ?? 30%. ????? anti-ssDNA (60%), anti-histone (70%), anti-Ro (SSA – 30%), anti-La (SSB - 15%), anti-RNP (35%). ?? ???? ???? ?? ?? ????????.

    48. Anti DNA antibodies in SLE Anti ss- DNA: nonspecific and not in clinical use Anti-ds DNA: specific for SLE Clinical use important: - levels correlate with disease activity - presence and level associated with risk for renal disease - pathogenic effect mediated through direct binding to glomeruli or immune-complex mechanisms. Anti-ssDNA – ?? ?????? ??? ??????, ????? ?? ?????? ???????? ?????. Anti-dsDNA – ??????, ??? ?????? ?????? ???? ???????? – ????? ???? ?????? ????? ????????. ?? ???, ??? ?? ?????? ????? ???? ???????? ????? ??????? (?????? ??? 14). ??? ???? ????????? ???????? ?????, ??? ???? ??? ?????? ?????.Anti-ssDNA – ?? ?????? ??? ??????, ????? ?? ?????? ???????? ?????. Anti-dsDNA – ??????, ??? ?????? ?????? ???? ???????? – ????? ???? ?????? ????? ????????. ?? ???, ??? ?? ?????? ????? ???? ???????? ????? ??????? (?????? ??? 14). ??? ???? ????????? ???????? ?????, ??? ???? ??? ?????? ?????.

    49. Clinical Associations of Auto-antibodies in SLE ?? ?????????? ??????? ???????? ??????? ??????: Anti-dsDNA (50%) ???? ?????? ?? ???????. Anti-ssDNA – ?? ??????, ??? ??????? ??????, ?? ??????. Anti-histone – ?? ?????, ?? ???? ?-drug induced lupus. Anti-Ro – ??? ??????? ?? sub-acute ?-heart block ?????. ??????? ??? ?????? ??? ????? ????? ??????? ???? ????. Anti-Sm (30%) – ??????, ?? ???????. Anti-RNP – mixed connective tissue disease. APLA – ???? ???? ?????, ?-30% ??????? ???? ?????????? ?? ???????? ?????? ??????.?? ?????????? ??????? ???????? ??????? ??????: Anti-dsDNA (50%) ???? ?????? ?? ???????. Anti-ssDNA – ?? ??????, ??? ??????? ??????, ?? ??????. Anti-histone – ?? ?????, ?? ???? ?-drug induced lupus. Anti-Ro – ??? ??????? ?? sub-acute ?-heart block ?????. ??????? ??? ?????? ??? ????? ????? ??????? ???? ????. Anti-Sm (30%) – ??????, ?? ???????. Anti-RNP – mixed connective tissue disease. APLA – ???? ???? ?????, ?-30% ??????? ???? ?????????? ?? ???????? ?????? ??????.

    50. Diagnosis of SLE Based on a combination of clinical manifestations and laboratory findings which may occur simultaneously or serially Classification criteria are used for research ????? ?? ????? ??? ????????? ?? ?????? ??????? ?????? ?????. ?? ?????? ?????? ?? ???? ?? ??????. ???? ?? ????????????? ?????? ?? ANA – ???? ????? ??? ??? ?????? ???? ????? ????? ?? ?????????, ??? ?? ????? ?? ??????. ????? ??????? ???? ?-suspected lupus, ?? ??? ?? ???? ?? ?? ???????????. ?????????? ????? ????? ?????? ????. ??????? ??????????? ??????? ?????? ??????.????? ?? ????? ??? ????????? ?? ?????? ??????? ?????? ?????. ?? ?????? ?????? ?? ???? ?? ??????. ???? ?? ????????????? ?????? ?? ANA – ???? ????? ??? ??? ?????? ???? ????? ????? ?? ?????????, ??? ?? ????? ?? ??????. ????? ??????? ???? ?-suspected lupus, ?? ??? ?? ???? ?? ?? ???????????. ?????????? ????? ????? ?????? ????. ??????? ??????????? ??????? ?????? ??????.

    51. Classification criteria of SLE Criterion Malar Rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Neurologic disorder Hematologic disorder Definition - Fixed erythema, malar distribution - Erythematous raised patches with scaling, atrophy, scarring - Skin rash as result of sunlight - Oral\ nasopharyngeal, usually painless - Nonerosive, 2 or more joints - Pleuritis OR Pericarditis -Proteinuria > 0.5gr or >+3 OR cellular casts - Seizures OR Psychosis - Hemolytic anemia OR Leukopenia < 4000/ mm3 OR Lymphopenia <1500/mm3 OR Thrombocytopenia < 100.000/mm3 ?????????? ?????? ???? 4/11 ????? ?????. ????? ????. ????? ??????????. ?????????????? – ????? ?????? ????. ????? ??? – ???? ???? ????', ?????? ??? ?? ????? ??? ?? ?????? ???. ???? ????? ?? ?? ??? ?????? ?? ?????. ???????? – ??? ???????, ???? ?????? ?? ????. ???????? – ????????? ?? ??????????. ???? – ?????? ?? ??????????? ?? ??? 0.5 ???. ?????????? – ???????. ????????? – ????? ????????, coombs ?????, ????????? ???? ?-4,000, ????????? ???? ?-1,500, ?????????????? ???? ?-100,000. ?????? – ???? ??????? anti-dsDNA, anti-Sm, false positive VDRL, APLA. ANA – ??? ???? ??????.?????????? ?????? ???? 4/11 ????? ?????. ????? ????. ????? ??????????. ?????????????? – ????? ?????? ????. ????? ??? – ???? ???? ????', ?????? ??? ?? ????? ??? ?? ?????? ???. ???? ????? ?? ?? ??? ?????? ?? ?????. ???????? – ??? ???????, ???? ?????? ?? ????. ???????? – ????????? ?? ??????????. ???? – ?????? ?? ??????????? ?? ??? 0.5 ???. ?????????? – ???????. ????????? – ????? ????????, coombs ?????, ????????? ???? ?-4,000, ????????? ???? ?-1,500, ?????????????? ???? ?-100,000. ?????? – ???? ??????? anti-dsDNA, anti-Sm, false positive VDRL, APLA. ANA – ??? ???? ??????.

    52. Classification criteria of SLE Criterion 10. Immunologic disorder 11. Anti-nuclear antibody Definition - anti-dsDNA OR - anti- Sm OR - false positive VDRL / anti-phospholipid antibody Abnormal titer of ANA in absence of drugs known to cause DIL

    53. Drug Induced Lupus Clinical manifestations of SLE that: - appear while taking a drug - resolve on discontinuation of the drug 10% of the incidence of SLE Clinical features are less severe than SLE. Common features: fatigue, weight loss, fever, arthritis, serositis, cytopenias. Uncommon features: CNS and renal involvement Drug induced ???? ?????? ??? ?????, ?? ????? ?? ????? ?????? (10% ???????? ?????). ?????? ?????: ?????? ???, ?????????, ????????, ????????. ??????? ???? ?? CNS ?????? ???? ??????.Drug induced ???? ?????? ??? ?????, ?? ????? ?? ????? ?????? (10% ???????? ?????). ?????? ?????: ?????? ???, ?????????, ????????, ????????. ??????? ???? ?? CNS ?????? ???? ??????.

    54. Drug Induced Lupus ANA-positive Anti-Histone - positive in > 90% nonspecific - found in SLE as well Anti-DNA - negative complement usually normal serology resolves slowly on drug discontinuation ??????: ANA ????? ?-anti-histone ????? ??? 90% ???????, ??? ?? ??????, ?? ????? ?? ?????? ????, ?? ?-anti-DNA ????? ??? ????? ??????. ???? ?????? ??????. ?-SLE ?? consumption ?? ????? ??????? ?????? (C4, C3) – ??? ????? ??? ?????. ?? ??? ???? – ???????, ??? ??????? – ?????. ?? ?? ??? ????, ?? ????????? ????? ????? ??????. ?-drug induced ??? ????. ????????? ????? ??? ???? ???? ???????? ?????? ??????.??????: ANA ????? ?-anti-histone ????? ??? 90% ???????, ??? ?? ??????, ?? ????? ?? ?????? ????, ?? ?-anti-DNA ????? ??? ????? ??????. ???? ?????? ??????. ?-SLE ?? consumption ?? ????? ??????? ?????? (C4, C3) – ??? ????? ??? ?????. ?? ??? ???? – ???????, ??? ??????? – ?????. ?? ?? ??? ????, ?? ????????? ????? ????? ??????. ?-drug induced ??? ????. ????????? ????? ??? ???? ???? ???????? ?????? ??????.

    55. Drugs associated with Drug Induced Lupus Definite: Hydralazine (5-10%) , Procainamide (15-20%), Chlorpromazine, Methyldopa, Isoniazid Possible association: Phenytoin, Penicillamine, Quinidine Questionable association: Gold salts, Griseofulvin ?????? ??????: hydralazine (??"?) ?-procainamide (?????? ???) ????. ????? ?????? ??????? ????, ????? ?? ?????? ?? ???, ???? ?????.?????? ??????: hydralazine (??"?) ?-procainamide (?????? ???) ????. ????? ?????? ??????? ????, ????? ?? ?????? ?? ???, ???? ?????.

    56. Management of SLE

    57. The Challenge Treat Active Lupus Prevent Damage from: - Active lupus - Corticosteroids - Immunosuppressive agents ????? ?? ???? ???? ?????? ?? ?-DD ??????. ???? ????? ??? ?????? ????. Damage index – ??? ????? ????? ???? ?????? ???????, ?? ?? ??????????? ??????????' ?????? ???. ???? ????? ?? ?? ????? ??????.????? ?? ???? ???? ?????? ?? ?-DD ??????. ???? ????? ??? ?????? ????. Damage index – ??? ????? ????? ???? ?????? ???????, ?? ?? ??????????? ??????????' ?????? ???. ???? ????? ?? ?? ????? ??????.

    58. Treatment of active SLE Organ System Approach Use the drug with the: - Least side effects - Lowest dose to control disease - Long term damage prevention Mild disease: Avoid Steroids Severe disease: Aggressive treatment ???? ???? ????? ????? ????? ????? ?????. ???? ?????? ?????? ???? ????? ?????, ?? ??? ?????? ????? ???? ??? ????? ???? (?? ?? ??? ?????? ?????? ?????). ?? ????? ??? – ?? ??? ?????????, ?? ????? ????? ??????? ?????. ?? ????? ??? – ?????????, ?????????? – ???? ????? ?????????.???? ???? ????? ????? ????? ????? ?????. ???? ?????? ?????? ???? ????? ?????, ?? ??? ?????? ????? ???? ??? ????? ???? (?? ?? ??? ?????? ?????? ?????). ?? ????? ??? – ?? ??? ?????????, ?? ????? ????? ??????? ?????. ?? ????? ??? – ?????????, ?????????? – ???? ????? ?????????.

    59. Treatments for SLE NSAIDs Corticosteroids Hydroxychloroquine (Plaquenil) Chloroquine (Aralen) Antimalarials Quinacrine ( Mepacrine; Atabrine) Methotrexate Azathioprine Cyclophosphamide Cyclosporine Mycophenolate Mofetil (Cellcept) IVIG Thalidomide ?????? NSAIDs – ???????, ??????. ???? ?????? ?????? ??????????. ??????? ???????? ????? ??????? ?????? ???. ?????????. ????-??????. ???????'. ??????? ?????????.?????? NSAIDs – ???????, ??????. ???? ?????? ?????? ??????????. ??????? ???????? ????? ??????? ?????? ???. ?????????. ????-??????. ???????'. ??????? ?????????.

    60. Corticosteroids Effective for the suppression of all SLE manifestations NOT justified for Arthritis Moderate doses (20-30mg\d) sufficient for: pleuritis\ pericarditis High doses (1mg\kg) required for: Nephritis, CNS disease, Severe hemolytic anemia or thrombocytopenia IV pulse 1gr methylprednisolone sometimes used for refractory nephritis or life threatening disease ????????? – ???? ??? ??????, ?? ?? ????? ??? ??????. ????????? ?????? NSAIDs ?????-??????! ???? ?????? ?????????? / ?????????? ???????? ????? ?? 200-30 ?"? / ?"?. ??????? ?????? ?? ????? ???????? ???, ????????????? ???, CNS – ?????? 1 ?"? / ?"?. Pulse therapy – 1 ??' ?? ???? ???????? ???????? ??? ?? ???? ????? ????.????????? – ???? ??? ??????, ?? ?? ????? ??? ??????. ????????? ?????? NSAIDs ?????-??????! ???? ?????? ?????????? / ?????????? ???????? ????? ?? 200-30 ?"? / ?"?. ??????? ?????? ?? ????? ???????? ???, ????????????? ???, CNS – ?????? 1 ?"? / ?"?. Pulse therapy – 1 ??' ?? ???? ???????? ???????? ??? ?? ???? ????? ????.

    61. Anti-Malarials Hydroxychloroquine, Chloroquine, Quinacrine Effective for the treatment of : Fatigue, Arthritis, Skin disease Prevents SLE flares Lowers cholesterol levels Anti-aggregant effect ???? ?????? ?????? ?-RA ???? ???? ??????. Hydroxychloraquie, chloroquine – ??????, quinacrine – ???, ?? ?? ????. ??????? ??????? ?????-?????? – ??????, ????????, ???? ???. ?? ?? ?????? ??????? ?? ?????. ???? ??? ?? ?? ?? ??????? – ??? ??? ???? ?? plaquinin ????? ?????? ????? (????? ??? ????? ?? ???? ?????). ??? ???? ???????????? ???? (?? ????? ??????).???? ?????? ?????? ?-RA ???? ???? ??????. Hydroxychloraquie, chloroquine – ??????, quinacrine – ???, ?? ?? ????. ??????? ??????? ?????-?????? – ??????, ????????, ???? ???. ?? ?? ?????? ??????? ?? ?????. ???? ??? ?? ?? ?? ??????? – ??? ??? ???? ?? plaquinin ????? ?????? ????? (????? ??? ????? ?? ???? ?????). ??? ???? ???????????? ???? (?? ????? ??????).

    62. Methotrexate May be effective as a steroid sparing agent in the treatment of: - arthritis - skin disease Methotrexate ?????? ????? ????? ?? ???? ????? ??? ????? ??? ?????-??????.Methotrexate ?????? ????? ????? ?? ???? ????? ??? ????? ??? ?????-??????.

    63. Used mainly for nephritis May be used for major organ involvement - Azathioprine: P.O. 2-3mg\kg - Cyclophosphamide : IV pulses 0.5-1.0gr/m2 q month than q3 months for 2-3 yrs - Cyclosporine: P.O. 1-3mg\kg\d - Mycophenolate Mofetil (Cellcept) : P.O. 1-3gr\d Immunosuppressive agents Azathioprine, Cyclophosphamide, Cyclosporine, Cellcept ???????' Azathioprine, Cyclophosphamide, Cyclosporine, Cellcept – ???? ?????? ??????, ?-cellcept ?? ???. ??????? ????? ???????? ??? ?-major organ involvement ???????? ?-steroid sparing – ??????? ?? ?????????? ??????? ?? ??????.???????' Azathioprine, Cyclophosphamide, Cyclosporine, Cellcept – ???? ?????? ??????, ?-cellcept ?? ???. ??????? ????? ???????? ??? ?-major organ involvement ???????? ?-steroid sparing – ??????? ?? ?????????? ??????? ?? ??????.

    64. Treatment of Lupus Nephritis Induction: - Corticosteroids - IV Cyclophosphamide \ q month - Mycophenolate Mofetil (Cellcept) ? Maintenance: - IV Cyclophosphamide \ q 3 mo - Azathioprine - Mycophenolate Mofetil ( Cellcept ) - Cyclosporine ????? ?????? ??????? ????? ???????? ??????, ??? ???? ???? ????? ??? ????? ???????. ??????? ?????? ???????????? – ????????? ?-maintenance. ?????????: ????????? ?? IV ?????' ??? ????? ???? ???. ??????: ?????' 3 ?????? ???? ?????? ????. ?? ?? ?????? ????? ?? ????? ???????, ?????? ????? ?????? ?????? ????, ???? ?? ?????? ??????: cellcept, ??????? ??????'.????? ?????? ??????? ????? ???????? ??????, ??? ???? ???? ????? ??? ????? ???????. ??????? ?????? ???????????? – ????????? ?-maintenance. ?????????: ????????? ?? IV ?????' ??? ????? ???? ???. ??????: ?????' 3 ?????? ???? ?????? ????. ?? ?? ?????? ????? ?? ????? ???????, ?????? ????? ?????? ?????? ????, ???? ?? ?????? ??????: cellcept, ??????? ??????'.

    65. Cyclophosphamide side effects Infection - frequency - 45% - sequential infusions - WBC < 3000 Premature ovarian failure - cumulative dose - age: < 25 yrs - 6% > 31 yrs - 67% Malignancy leukemia, gynecologic malignancies, bladder ?????? ????? ?? ?????' IV – ??????? ??? ????????? ??????'. ?"? ?????? – ???? ??? ???? ????? ?????? (6% ???? ???? 25, ???? 67% ?? ???? ?????? ??? ??? 31). ??? ????? ????? ????? ???? ????????? ?? ????? ?????, ?? ????? ????? ??"? ????? ??? ????? ??. ?????????, ????? ?? ????????.?????? ????? ?? ?????' IV – ??????? ??? ????????? ??????'. ?"? ?????? – ???? ??? ???? ????? ?????? (6% ???? ???? 25, ???? 67% ?? ???? ?????? ??? ??? 31). ??? ????? ????? ????? ???? ????????? ?? ????? ?????, ?? ????? ????? ??"? ????? ??? ????? ??. ?????????, ????? ?? ????????.

    66. Mycophenolate Mofetil ( MMF = Cellcept) Immunosuppressive for: kidney, liver and heart transplant Inhibitor of : Inosine Monophosphate (IMP) dehydrogenase - key enzyme in de novo purine synthesis - glycosylation of adhesion molecules in T and B cells Inhibits: - proliferation of T and B lymphocytes - production of abs - generation of cytotoxic T cells - recruitment of leukocytes to sites of inflammation MMF ?-cellcept ????? ???????, ????? ???????' ?????? ????? ???, ?? ?????. ???? inosine monophosphate dehydrogenase (??????? ???????), ???? ???? ???? ????: T, B, ???????, ???? ??????????.MMF ?-cellcept ????? ???????, ????? ???????' ?????? ????? ???, ?? ?????. ???? inosine monophosphate dehydrogenase (??????? ???????), ???? ???? ???? ????: T, B, ???????, ???? ??????????.

    67. MMF or IV Cyclophosphamide for Lupus Nephritis Ginzler et al. NEJM 2005 140 pts class III, IV, V (24 week trial) MMF (71 pts) CTX (69 pts) At 12 weeks: - Complete remission 16 4 - Partial remission: 21 17 - Death 0 3 - Severe infections 1 6 - Diarrhea 15 2 Conclusion: - MMF more effective than CTX in inducing remission - severe infections : less with MMF ????: 71 ????? ????? cellcept ??? ?????', ???? ???? ???????, ?? ???? ????, ???? ???????, ??-????? ???????. ???? ???? ?????? ?????' ??????? ????????.????: 71 ????? ????? cellcept ??? ?????', ???? ???? ???????, ?? ???? ????, ???? ???????, ??-????? ???????. ???? ???? ?????? ?????' ??????? ????????.

    68. Sequential Therapies for proliferative LN Contreras G et al. NEJM 2004 59 patients: class: III-12; IV-46; Vb-1 Induction: IV CYC (0.5-1gr/m2) q mo for up to 7 pulses + steroids Maintenance (1-3 yrs): - IV CYC q 3 months - AZA 1-3 mg/kg/d - MMF 0.5-3 gr/d ????? ????????? ?? ?????'. ????? ?????? ?? ????? ???? ???????? ??? ??????? ?? cellcept.????? ????????? ?? ?????'. ????? ?????? ?? ????? ???? ???????? ??? ??????? ?? cellcept.

    69. Future possible treatments for SLE Treatments designed to effect specific processes LJP 394: B cell toleragen: cross links anti-DNA receptors on B cells Anti IL-10: IL-10 is increased on correlates with disease activity Anti-CD40 ligand: prevents T cell activation CTLA4Ig: blocks CTLA4 on activated T cells from binding to B7 on B cells Anti C5 complement C1q immunoadsorption: removes immune complexes Anti CD 20 (Rituximab):CD20 is B cells restricted ag- leads to B cell depletion Anti-BLyS: anti B Lymphocyte Stimulator protein which is elevated in SLE 40 ??? ?? ??? ????? ?????? ??????. ???? ????? ???? ??????? ???????? ??????, ??? ??? IL-10. ???? anti-CD20 (rituximab ????????), ???? depletion ?? ??? B, ?? ?????? ????? ???? ?????? ??????. Anti-BLyS – ????? ?????? ?? ??? B (?? ???? depletion) ??? ????? ????? ??? ?? ??' ?????? ??? depleteion.40 ??? ?? ??? ????? ?????? ??????. ???? ????? ???? ??????? ???????? ??????, ??? ??? IL-10. ???? anti-CD20 (rituximab ????????), ???? depletion ?? ??? B, ?? ?????? ????? ???? ?????? ??????. Anti-BLyS – ????? ?????? ?? ??? B (?? ???? depletion) ??? ????? ????? ??? ?? ??' ?????? ??? depleteion.

    70. Corticosteroids- the price: Avascular Necrosis of Bone Osteoporosis with Fracture Hypertension, Hyperglycemia Premature Atherosclerosis Quality of life: Weight, Cushingoid Habitus, Mood changes ?????? ??? ???? ????? ??????, ????? ????? ????? ???? ???? ?????? ???? ???? ?? ?????? ?????. ????? ?????? ????????? ????? ????????????, a-vascular necrosis, ?????????????, ???????????? – ?????? ?? ????? ?????.?????? ??? ???? ????? ??????, ????? ????? ????? ???? ???? ?????? ???? ???? ?? ?????? ?????. ????? ?????? ????????? ????? ????????????, a-vascular necrosis, ?????????????, ???????????? – ?????? ?? ????? ?????.

    71. Distribution of Damage Johns Hopkins Cohort 25.2% musculoskeletal 15.0% neuropsychiatric 12.6% ocular 11.7% renal 10.4% pulmonary 10.1% cardiovascular 7.4% gastrointestinal 7.4% skin 6.1% diabetes 2.5% malignancy 1.2% premature gonadal failure ??? ????? ?????? ??? ??? = ????? ???? ????? ?????. ????????????? (25%) – a-vascular, ?????????????. ?????-???????? ????? ??????? ????? ?????? ?????? – ????????, ????? (?????????).??? ????? ?????? ??? ??? = ????? ???? ????? ?????. ????????????? (25%) – a-vascular, ?????????????. ?????-???????? ????? ??????? ????? ?????? ?????? – ????????, ????? (?????????).

    72. SLICC Damage Index SLICC: Systemic Lupus International Collaborating Clinics Damage = nonreversible change not related to active inflammation, present for 6 months Damage index (SLICC) - ??? ???? ???? ???? ??? ??? ??????? ?????? ??.Damage index (SLICC) - ??? ???? ???? ???? ??? ??? ??????? ?????? ??.

    73. Damage in SLE - Coronary Artery Disease Major cause of morbidity Bimodal pattern of mortality in SLE: early - due to disease and infection late - due to Cardiovascular disease prevalence: 8-10% Hydroxychloroquine- may be protective: reduces cholesterol, anti-aggregation properties ???? ?????? ????? ????????? ??? ???? ?????. ???? ????? ???????? ?"? ??? ?????'. Plaquinin ???? ????? ???.???? ?????? ????? ????????? ??? ???? ?????. ???? ????? ???????? ?"? ??? ?????'. Plaquinin ???? ????? ???.

    74. Prevalence of cardiovascular disease in SLE Hospitaliztion of young SLE women compared to non SLE: - 2-3 times more likely to have MI - 3.8 times more likely to have CHF - 2.1 times more likely to have CVA SLE women age 35-44: 50 times more likely to have MI compared to women of similar age (Framingham offspring study) ????? ????? ?? 2 ???? ???????? ???? MI, ?? 3.8 ???? CHF ??? 2.1 ???? CVA. ?? ?? 50 ???? ????? ?-MI. ?? ?? ?????? ????? – ???? ????? ?? ???? ??????, ???"? ???? ?? ???? (????: ICD ?????? ?? 35 ??????? ????? ???? 16).????? ????? ?? 2 ???? ???????? ???? MI, ?? 3.8 ???? CHF ??? 2.1 ???? CVA. ?? ?? 50 ???? ????? ?-MI. ?? ?? ?????? ????? – ???? ????? ?? ???? ??????, ???"? ???? ?? ???? (????: ICD ?????? ?? 35 ??????? ????? ???? 16).

    75. Risk factors for cardiovascular disease in SLE Hypertension Hyperlipidemia Diabetes Mellitus Obesity Active SLE: - chronic inflammation leads to endothelial damage - anti-endothelial abs, anti-phospholipid antibodies ??????? ?????-?????????? ???? ??????? – ??"?. ????????????. ?????? ?????? ?????? ???? ??? ???? ??????, ??? ??????? ???? ?????? ??? ?-APLA ?? ????? ????????????? ?????. ???? ?????? ?? ?? ????? ??????: ????? ?????', ?????, ????? ?"? ????? ??????? – ??? ????? ????? ????? ?? ??????? ???, ???? ??? ???? ?????.??????? ?????-?????????? ???? ??????? – ??"?. ????????????. ?????? ?????? ?????? ???? ??? ???? ??????, ??? ??????? ???? ?????? ??? ?-APLA ?? ????? ????????????? ?????. ???? ?????? ?? ?? ????? ??????: ????? ?????', ?????, ????? ?"? ????? ??????? – ??? ????? ????? ????? ?? ??????? ???, ???? ??? ???? ?????.

    76. Prognosis Survival: 90-95% at 2 years 82-90% at 5 years 71-80% at 10 years 63-75% at 20 years Poor prognostic factors: - creatinine, nephrotic syndrome - hypertension - thrombocytopenia - African- American race - low socioeconomic status ????????? ???? ?????. ????? ??????????? ????: ???????? ????, ?????? ???????, ??????????????, ???? ????-??????? (????? ????, ?????? ???? ??? ?????? ?? ???? ?????? ??????), ??? ?????-??????? ???? (???? ?????? ?????).????????? ???? ?????. ????? ??????????? ????: ???????? ????, ?????? ???????, ??????????????, ???? ????-??????? (????? ????, ?????? ???? ??? ?????? ?? ???? ?????? ??????), ??? ?????-??????? ???? (???? ?????? ?????).

    77. ?????? – ???? ???????? ?? ?????.?????? – ???? ???????? ?? ?????.

    78. Pregnancy and SLE 1950s: - in SLE: pregnancy is not advised - termination should be offered 1990s: - 10-30% flare during pregnancy / postpartum - most flares are minor ?????? ??? ????' ??? ???? ?????? ?? ????? ???? ???????. ???????? ???? ????? ???????, ?? ?? ?????? ?????? ?????? ???????. ????? ?-50' ???? ????? ??? ????? ?????. ??? ????? ?-90' ??????? ???? ?????? ??????? ??? 10-30% ??????? ??????? ?? ???? ?????, ????? ???? ?? ??????? ?????? ????.?????? ??? ????' ??? ???? ?????? ?? ????? ???? ???????. ???????? ???? ????? ???????, ?? ?? ?????? ?????? ?????? ???????. ????? ?-50' ???? ????? ??? ????? ?????. ??? ????? ?-90' ??????? ???? ?????? ??????? ??? 10-30% ??????? ??????? ?? ???? ?????, ????? ???? ?? ??????? ?????? ????.

    79. Q: Which statement is incorrect regarding pregnancy in lupus SLE patients are less fertile ( low fertility rate) SLE patients have higher frequency of premature labor. 3. SLE may flare during pregnancy and postpartum 4. Neonatal lupus occurs due to transplacental transmission of maternal auto-abs 5. Most well controlled lupus patients can become pregnant and give birth to healthy children ?? ???????? ????? ?? ???? ???? ???? ???????? ????? ???? ?????? ????? ????. ?? ???? ?????? ?????? ??????, ?? ??? ???? ??? ??? ????? ???????.?? ???????? ????? ?? ???? ???? ???? ???????? ????? ???? ?????? ????? ????. ?? ???? ?????? ?????? ??????, ?? ??? ???? ??? ??? ????? ???????.

    80. Pregnancy Outcomes in SLE Johns Hopkins Cohort Fertility rates: normal 2-2.4 pregnancies\patient Preterm < 37 weeks 40.5% < 36 weeks 32.1% Pregnancy loss 10-30% 1st trimester 6.0% 2nd trimester 7.1% ?? ???? ????? ??????? ????? ?????. ?????? ??? ????? ?? ????? ?????? ????? ????? ??? ??? ???? ?????.?? ???? ????? ??????? ????? ?????. ?????? ??? ????? ?? ????? ?????? ????? ????? ??? ??? ???? ?????.

    81. The Mother in SLE Risk factors for exacerbation: - active disease 3-6 months before conception - pre-existing renal disease Conception during remission: 10-30% risk of flare. Mild lupus rarely exacerbates in pregnancy Severe exacerbations: in 20% of pregnancies ??????? ????? ?????? ??????? ???????? ???? ????. ?????? ?????? ???? ????? ???? ??? ???? ??????? ?? ?? ?? ???? ??????? ?????, ?? ????? ?????? ?? ??? ??? ?? ?? 10-30% ????? ???????? (??? ??? ???). ????????? ???? ??????? ?-20% ??????????. ????? ??????? ????? ???? ????? ????? ???? ??????.??????? ????? ?????? ??????? ???????? ???? ????. ?????? ?????? ???? ????? ???? ??? ???? ??????? ?? ?? ?? ???? ??????? ?????, ?? ????? ?????? ?? ??? ??? ?? ?? 10-30% ????? ???????? (??? ??? ???). ????????? ???? ??????? ?-20% ??????????. ????? ??????? ????? ???? ????? ????? ???? ??????.

    82. Management of SLE flares in pregnancy Prednisone IV Pulse methylprednisolone NSAIDs ( during 1st trimester ) Plaquenil Azathioprine Cyclosporine ??????? ???? ??? ?????????, NSAIDs ???????? ?????, plaquinin (???? ???? ??? ?? ????? ?? ??? ??????? ?? ????? ???? ??????), ??????? (?? ????? ?? ?? ????), ?????' – ?? ??? ?????.??????? ???? ??? ?????????, NSAIDs ???????? ?????, plaquinin (???? ???? ??? ?? ????? ?? ??? ??????? ?? ????? ???? ??????), ??????? (?? ????? ?? ?? ????), ?????' – ?? ??? ?????.

    83. Neonatal Lupus 1. Neonatal cutaneous lupus 2. Congenital heart block Due to placental transmission of maternal IgG abs Occurs in women with: - anti Ro\SSA , anti La\SSB, anti U1 RNP Prevalence of neonatal lupus in mothers with the auto-abs: 2-5% The mother may be : asymptomatic, have: SLE, Sjogren syn, other rheumatic disease. Neonatal lupus ???? ???????? ?????? ?????. ???? ????? ???? ????? ???? ?? heart block. ?? ?? ???? ??? ???????, ???? ???? ????? ???? ?? ?? ?????? (???? ??? ????). ???????? ???????? anti Ro, anti La, anti RNP. ?????? neonatal lupus ??????? ?? ??????? ?????? 2-5%. ??????? ?????? ????? ?????? ????? ????? ??? ??? ????? ?? ???? ???????? ?? ??????? ???. ???? ????? ??????? ??? ???? ???????.Neonatal lupus ???? ???????? ?????? ?????. ???? ????? ???? ????? ???? ?? heart block. ?? ?? ???? ??? ???????, ???? ???? ????? ???? ?? ?? ?????? (???? ??? ????). ???????? ???????? anti Ro, anti La, anti RNP. ?????? neonatal lupus ??????? ?? ??????? ?????? 2-5%. ??????? ?????? ????? ?????? ????? ????? ??? ??? ????? ?? ???? ???????? ?? ??????? ???. ???? ????? ??????? ??? ???? ???????.

    84. Neonatal cutaneous lupus Neonatal cutaneous lupus – ???? ??? sub-acute cutaneous. ???? ?????? ?????? ??? ???? ?????????? ?????? ?????? ???.Neonatal cutaneous lupus – ???? ??? sub-acute cutaneous. ???? ?????? ?????? ??? ???? ?????????? ?????? ?????? ???.

    85. Congenital heart block (CHB) Prevalence: 1:20,000 births ( 0.005%) anti Ro \ anti La + should have weekly echocardiographies at 18-25 weeks complete block: in 90% of reported cases 60% require pacemakers, 30%-die recurrence - 13% Congenital heart block – ???? ????, ???? ????? ???? ????? ??????? ?"? US. ???? ??????? ???? ???? 13%, ???? ????? ???.Congenital heart block – ???? ????, ???? ????? ???? ????? ??????? ?"? US. ???? ??????? ???? ???? 13%, ???? ????? ???.

    86. Management of congenital heart block Prophylactic treatment of high risk mother - not helpful. Treatment of identified block: T. Dexamethasone 4mg\d Rationale for treatment of identified block: - reduce generalized inflammatory insult - lower titer of maternal auto-abs. ??? ??? ??? ????? ????????? ????? ????. ?? ?????? ??? ?????? dexamethazone ?? ???? ????, ????? ?????? ??? ??????? ??? ????? ????? ????????. ????? ??? ????? ???.??? ??? ??? ????? ????????? ????? ????. ?? ?????? ??? ?????? dexamethazone ?? ???? ????, ????? ?????? ??? ??????? ??? ????? ????? ????????. ????? ??? ????? ???.

    88. Female, 19 years old single, Israeli born 1995: Fever Sore throat Polyarthritis Systolic murmur 2/6 Initial working diagnosis: Rheumatic Fever ????: ?????? ????? ???? 19 ??? ?? ???, ??? ????, ???????? ???????. ???? ??? ?? rheumatic fever ????? ????'.????: ?????? ????? ???? 19 ??? ?? ???, ??? ????, ???????? ???????. ???? ??? ?? rheumatic fever ????? ????'.

    89. History and laboratory work-up Weight loss, fatigue Hair loss for past months, photosensitive rash Raynaud’s phenomenon Lab: ANA +, anti-DNA - 30%, low C3 CBC, chemistry, urine - normal anti-cardiolipin IgG -positive lupus anticoagulant- positive Echocardiogram: mild mitral regurgitation ????? ??? ?? RF: ????? ?????, ???? ?????, ????? ???? ????? ??????? ???????, ????? ??????? ????, ?????? raynaud (???? ??? ?????? ??????). ???? ?? ???? ????? ?????? ??? ???????? ?? ??? ???. ????? ?????? ????? ??????? ANA ?????, ????-??"? ?????, ????? ???? (????? ????? consumption), ??? ????, ???? APLA, ???? ?"? ???????? ???. ?? ?? ??????????: ????????, ANA, anti-DNA, APLA. ??? ?? ??? ????, ?? ??? ?? ???? ???????.????? ??? ?? RF: ????? ?????, ???? ?????, ????? ???? ????? ??????? ???????, ????? ??????? ????, ?????? raynaud (???? ??? ?????? ??????). ???? ?? ???? ????? ?????? ??? ???????? ?? ??? ???. ????? ?????? ????? ??????? ANA ?????, ????-??"? ?????, ????? ???? (????? ????? consumption), ??? ????, ???? APLA, ???? ?"? ???????? ???. ?? ?? ??????????: ????????, ANA, anti-DNA, APLA. ??? ?? ??? ????, ?? ??? ?? ???? ???????.

    90. Treatment and Course Plaquenil 200 mg x 2\d Naxyn 500 mg X 2\d nearly asymptomatic for 1 year ????? ?? plaquenil ?????-?????????? ????? ??????.????? ?? plaquenil ?????-?????????? ????? ??????.

    91. 1996: Flare Polyarthritis elevated anti-DNA ( 87%) low complement microscopic hematuria, RBC casts, proteinuria: 1.7 gr/24 hrs preserved CCT Kidney biopsy: focal proliferative glomerulonephritis ( Class III) ???? ??? ????? ?? ???????: ????? ?????, ???????, ?????? ?? ??????? ??????, ????? ?????? ????. ???? ??? – ???????, ????? FPGN ????? 3. ?? ????? ????? ?? ????? ??? ?? ????, ?? ?? ????? ?????? – ?? ?? ????? ????? ???? ??? ?????.???? ??? ????? ?? ???????: ????? ?????, ???????, ?????? ?? ??????? ??????, ????? ?????? ????. ???? ??? – ???????, ????? FPGN ????? 3. ?? ????? ????? ?? ????? ??? ?? ????, ?? ?? ????? ?????? – ?? ?? ????? ????? ???? ??? ?????.

    92. Treatment T. Prednisone 60 mg\d IV Cyclophosphamide 500mg\m2 - once a month for 6 months - once every 3 months Continue: Plaquenil 200mg x 2\d ???? ???? ???????? – ????????, ?????? ?-plaquenil (??????).???? ???? ???????? – ????????, ?????? ?-plaquenil (??????).

    93. Course Initial response: resolution of arthritis and proteinuria persistent hematuria normalization of C3 C4, drop in anti-DNA (22%) prednisone dose tapered to 12.5 mg\d ????? ????? – ???? ??????.????? ????? – ???? ??????.

    94. 1997: Flare 1 week prior to 8th CTX pulse Polyarthritis severe nephrotic syndrome: proteinuria: 11gr\24hrs albumin: 2.0 gr\dl microscopic hematuria drop in complement rise in anti-DNA - 45% ??? ?????? ??? ??? ????????? ???????? ??????. ??????????? ?? 11 ??', ?????? ????, anti-DNA ????. ?? ?????? ??? ??? ????? ????????.??? ?????? ??? ??? ????????? ???????? ??????. ??????????? ?? 11 ??', ?????? ????, anti-DNA ????. ?? ?????? ??? ??? ????? ????????.

    95. Histologic class transformation? Repeat kidney biopsy- suggested but not done due to: non- occluding Renal Vein Thrombosis 2 episodes of pleuritic chest pain- suspected Pulmonary embolism ????? ????? ??????? ????? – ???? ?? ?? ???????? ???? ??? ????. ??? ????? ?? ????? ???? ???? ???? renal vein thrombosis. ??? ?????? ??? ???????? ???? ????? ?? ?-PE (?? ???? ????).????? ????? ??????? ????? – ???? ?? ?? ???????? ???? ??? ????. ??? ????? ?? ????? ???? ???? ???? renal vein thrombosis. ??? ?????? ??? ???????? ???? ????? ?? ?-PE (?? ???? ????).

    96. Treatment IV Heparin, followed by Warfarin ( INR-2.5) IV pulse Methylprednisolone 1 gr\d for 3 days followed by Prednisone 60 mg\d IV pulse Cyclophosphamide 800 mg\m2 once a month ???? ????? ?????? ????? ??? ?????? (?? ???? ????? ??????? ?? ????-??????????). ????? pulse ?? ?????????. ????? ????? ????????? ??? ????? ?????? ???? ????.???? ????? ?????? ????? ??? ?????? (?? ???? ????? ??????? ?? ????-??????????). ????? pulse ?? ?????????. ????? ????? ????????? ??? ????? ?????? ???? ????.

    97. Course Gradual improvement in proteinuria - 2 gr\24 hrs normalization of anti-DNA, increase in C3 C4 Avascular necrosis - both knees, both shoulders after 3 months: Cyclophosphamide switched to Azathioprine Prednisone tapered to 15 mg\d ??? ???? ?-11 ??' ????? ?-2 ??'. ??? ????? ????? ????????? – a-vascular necrosis ???? ??????? ???? ??????? ??????. ???? 3 ?????? – ?????? ????? maintenance ???????? (?? ??? ????? ???? ???? ????????, ?? ??? ???? ????? ?????).??? ???? ?-11 ??' ????? ?-2 ??'. ??? ????? ????? ????????? – a-vascular necrosis ???? ??????? ???? ??????? ??????. ???? 3 ?????? – ?????? ????? maintenance ???????? (?? ??? ????? ???? ???? ????????, ?? ??? ???? ????? ?????).

    98. 1998: Flare Pancytopenia Nephrotic syndrome: - protein 5.5 gr\24hrs - albumin 1.2 gr\dl - anasarca Treatment: IV pulse methylprednisolone 1 gr/ 3 days IV cyclophosphamide 1000 mg/m2 ????? ??? ?? ???????????. ?? ?? ????????? – ???? ?????? ?? ??????, ??? ?? ?????? – ???? ?????? ?? ??????. ????? anasarca ?? ??????? 1.2, ??????????? ???. ??? ???? ????????? ???? ????? ?????? (?? ??? ?? cellcept, ??? ??????? ??).????? ??? ?? ???????????. ?? ?? ????????? – ???? ?????? ?? ??????, ??? ?? ?????? – ???? ?????? ?? ??????. ????? anasarca ?? ??????? 1.2, ??????????? ???. ??? ???? ????????? ???? ????? ?????? (?? ??? ?? cellcept, ??? ??????? ??).

    99. Course Neutropenic fever - post cyclophosphamide - resolved with antibiotics No improvement in proteinuria or activity of disease. Management?? ????? neutropenic fever ??????????, ??? anasarca. ???? ?"? ???????????. ??? ???????????? ?????, ??? ???????????? ???? ???? ????? ????????. ?????? ?? ????? renal shutdown.????? neutropenic fever ??????????, ??? anasarca. ???? ?"? ???????????. ??? ???????????? ?????, ??? ???????????? ???? ???? ????? ????????. ?????? ?? ????? renal shutdown.

    100. Treatment Supportive: IV salt free albumin high dose diuretics ACE inhibitors Cyclosporine - 5 mg\kg Prednisone - 60 mg\d ???? ?? ????? ????: ???????? ????????. ???? ?? ???????????, ???? ??????.???? ?? ????? ????: ???????? ????????. ???? ?? ???????????, ???? ??????.

    101. Course Gradual marked improvement: resolution of pancytopenia resolution of proteinuria, normalization of albumin normalization of anti-DNA and complement persistent microscopic hematuria ???????????? ?????, anti-DNA ??? ??????, ????? ?? ???????, ?? ???? ?? ????????? (???? ???? AVN ???).???????????? ?????, anti-DNA ??? ??????, ????? ?? ???????, ?? ???? ?? ????????? (???? ???? AVN ???).

    102. Problems unable to reduce prednisone below- 12.5 mg\d unable to reduce cyclosporine doses Azathioprine added as steroid sparing and “cyclosporine sparing” ??? ???? ?????? ?? ?-gingiva, ?????????.??? ???? ?????? ?? ?-gingiva, ?????????.

    103. Course Remission for 18 months no proteinuria, normal anti DNA, C3, C4 Planned pregnancy Treatment during pregnancy: Plaquenil, Azathioprine, Prednisone 10mg\d Low molecular weight Heparin Delivered healthy baby at term Mild flare 2 months postpartum: proteinuria < 1 gr\d Controlled with prednisone ???? ?????? ?? ??"?, C3, C4 ??????, ????? ???. ???? ?? plaquenil ?? ???????, ???? ???????, ?? ???? ??? ?????? ???????. ???? ????? ???? ??????, ???? ?? ??????? ??? ??? ???? ????? (??????????? ?? ???? ?-1 ??'). ???? ?? ?? ??? ???.???? ?????? ?? ??"?, C3, C4 ??????, ????? ???. ???? ?? plaquenil ?? ???????, ???? ???????, ?? ???? ??? ?????? ???????. ???? ????? ???? ??????, ???? ?? ??????? ??? ??? ???? ????? (??????????? ?? ???? ?-1 ??'). ???? ?? ?? ??? ???.

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