Systemic Lupus Erythematosus 류마티스내과 R3 신재령

Introduction  SLE 소개  Lupus nephritis  Antiphospholipid Syndrome

Definition  SLE : autoimmune disease in which organs, tissues, cells undergo damage mediated by tissue-binding autoantibodies and immune complexes “Lupus”  Latin for “wolf”  Erosive skin lesions that ate away the flesh and were evocative of a wolf’s bite.

Etiology Genetic factor Hormonal factor Environmental factor Immunologic factor SLE ? ? ? ?

N Engl J Med 2008;358: Mechanisms of SLE

February 2012 Vol 8 No 2 Nature reviews rheumatology

Symptoms suggestive of SLE ANA, CBC, U/A ANA (+) All test (-) SLE Organ-/life- threatening Not organ-/life- threatening Symptoms persist Repeat ANA Anti-dsDNA Anti-Ro All test (-) Not SLE High-dose steroid, Immunosuppressive therapy

Autoantibodies in SLE Harrison's Principles of Internal Medicine (18 th ) Table 319-1

 1982 ACR criteria 1.Malar rash 2.Discoid rash 3.Photosensitivity 4.Oral ulcer 5.Arthritis 6.Serositis (pleuritis, pericarditis) 7.Renal disorder ◦ persistent proteinuria ≥0.5g/d or (+++) ◦ Cellular cast 8.Neurologic disorder (seizures, psycosis) 9.Hematologic disorder ◦ hemolytic anemia, thrombocytopenia ◦ leukopenia, lymphopenia 10.Immunologic disorder ◦ LE(+), anti-dsDNA, anti-Sm, false(+)syphilis 11.Antinuclear antibody Any 4 or more 11 criteria are present, serially of simultaneously, during any interval of observation Criteria 1~4 must have been present for at least 6 weeks  SLICC revised ACR criteria Clinical criteria 1. Acute or subaute cutaneous lupus 2. Chronic cutaneous lupus 3. Oral/nasal ulcers 4. Nonscarring alopecia 5. Inflammtory synovitis 6. Serositis 7. Renal disease 8. Neurologic diseases 9. Hemolytic anemia 10. Leukopenia or lymphopenia 11. Thrombocytopenia Immunologic criteria 1. ANA 2. Anti-dsDNA 3. Anti-Sm 4. Antiphospholipid antibody 5. Low compliment 6. Direct Coombs test The patients has 1) biopsy-proven lupus nephritis With ANA or anti-dsDNA, 2) 4 of criteria, including at least 1 clinical and 1 immunologic criterion Diagnosis

Clinical manifestations

Malar rash  Acute onset  Fixed erythema, flat or raised  Over the malar eminences  Sparing the naso-labial folds  Pruritic or painful Photosensitivity  Exposure to UV light causes rash Clinical manifestations (malar rash)

 Erythematous raised patches with adherent keratotic scaring and follicular plugging Clinical manifestations (discoid rash)  Atrophic scarring may occur

 Non-fixed  Non-scarring  Exacerbating and remitting  Erythematous papules or small plaques with a slight scale  Intermediate between acute and chronic lesions Clinical manifestations (subacute cutaneous LE) 사진

 Oral and nasopharyngeal ulcer  Usually painless  Observed by physician Clinical manifestations (oral ulcer)

 Non-erosive arthritis  Intermittent polyarthritis  Tenderness, swelling, effusion, deformity Swan neck deformitiesDeforming lupus arthritis Clinical manifestations (arthritis)

 Pleuritis (50%) with/without effusion  Pericarditis: ECG, rub, evidence of pericardial effusion Initial after treatment of lupus pericarditis Clinical manifestations (serositis)

Pulmonary fibrosis  SLE with lung involvement must always be evaluated for infection, particularly that due to bacteria, tuberculosis and viruses Lupus pneumonitis Clinical manifestations (pulmonary involvement)

 Abnormal urinalysis : 50% at the time of diagnosis : eventually develops in ≥ 75 %  Proteinuria : 80%  Hematuria and/or pyuria : 40%  Lupus nephritis : 50-70% Granular cast RBC cast Cellular cast Clinical manifestations (renal involvement)

 Is it related to SLE or not ?  Diffuse process or vascular occlusive disease ? Clinical manifestations (neuropsychiatric disorder)

 Hemolytic anemia with reticulocytosis : rapid in onset and severe : well response to high-dose glucocorticoid therapy  Leukopenia < 4,000/mm 3 on 2 occasions  Lymphopenia < 1,500/mm 3 on 2 occasions  Thrombocytopenia < 100,000/mm 3  Anemia due to chronic illness : most frequent Clinical manifestations (hematolgic disorder)

 Cutaneous  Mesenteric  Retinal … Cotton wool spots Hemorrhage Arterial occlusion Clinical manifestations (vasculitis)

Ju, J. H. et al. Nat. Rev. Rheumatol. 5, 273–281 (2009) lupus mesenteric vasculitis

 Arterial & venous  Cardiovascular risk   Associated with anti-phospholipid Ab Clinical manifestations (vascular thrombosis)

normal hemorrhage dilated capillaries Clinical manifestations (Raynaud`s phenomenon)

Assessment of disease activity  titers of anti-dsDNA Ab  complement level (C3, C4, CH50)  soluble IL-2 level  urinary MCP-1 (monocyte chemotactic protein-1) level  Indicators of organ involvement : hemoglobin levels, platelet counts, urinalysis, serum levels of creatinine or albumin

Management  No cure, rare complete remission  Management Goal : maintain organ function Mild diseaseLife or organ threatening disease Fever CNS involvement Arthritis Significant renal disease Rash Lupus pneumonitis, hemorrhage Pleuropericardial effusion Acute vasculitis Mild pericarditis Myocarditis Fatigue Massive pleural/pericardial effusion Oral ulcer Hemolytic anemia (marked) HeadacheThrombocytopenic purpura

Management (mild disease)  Fever : NSAIDs  antimalarials  steroids  Arthralgia/myalgia : NSAIDs  acetaminophen  amitriptyline  Arthritis : NSAIDs  antimalarials  steroids or MTX  Rashes : sunscreens  topical steroids  antimalarials  injection  Oral ulcers : antimalarials  Raynaud’s : no smoking, caffeine, decongestants  warm clothing  biofeedback  (long-acting) nifedipine  prazosin…

 Serositis : indomethacin  steroids  Pulmonary : steroids  Hypertension : diuretics  ACE inhibitors  calcium channel blockers  vasodilators  Thrombocytopenia/hemolytic anemia : steroids  pulse steroids  immunosuppressives  CNS disease 1) organic : steroids  antiseizures drugs  immunosuppressives 2) functional : antianxiety, antidepression drugs Management (Life or organ threatening disease)

Prognosis  Survival in lupus : 90-95% (2 years), 82-90% (5 years), 71-80% (10 years), 63-75% (20 years)  Poor prognosis : High serum Cr level (>1.4mg/dl), Hypertension Nephrotic syndrome (proteinuria >2.6g/day) Anemia (Hb<12.4g/dl) Hypoalbuminemia, Hypocomplementemia anticardiolipin antibody (aCL) African-American women

Lupus nephritis

Diagnosis : Persistent proteinuria 0.5 gm per day or greater than 3 by dipstick, and/or RBC casts + renal biopsy 표

Mesangial lesions (class II) Focal proliferative Glomerulonephritis (class III) Diffuse proliferative Glomerulonephritis (class IV) Membranous glomerulonephritis (class V)

Mesangial lesions (class II) Focal proliferative Glomerulonephritis (class III) Diffuse proliferative Glomerulonephritis (class IV) Membranous glomerulonephritis (class V)

Histological index of lupus nephritis Potentially reversible irreversible

Management of lupus nephritis Kidney International (2006) 70, 1403–1412

Antiphospholipid Syndrome

Antiphospholipid syndrome Antiphospholipid antibody syndrome (APS)  Recurrent arterial or venous thromboses and/or pregnancy morbidity with the persistent presence of anticardiolipin antibodies or lupus anticoagulant Major types of antiphospholipid antibody  False positive serologic test for syphilis  Lupus anticoagulant : positive in 30% of lupus  Anticardiolipin antibody : positive in 40-47% of lupus  Anti-β 2 - glycoprotein I antibody

Diagnosis N Engl J Med 2002; 346:

Clinical manifestations of APS  Deep vein thrombosis - 32 %  Thrombocytopenia - 22 %  Livedo reticularis - 20 %  Stroke - 13 %  Superficial thrombophlebitis - 9 %  Pulmonary embolism - 9 %  Fetal loss - 8 %  Transient ischemic attack - 7 %  Hemolytic anemia - 7 % Thrombotic microangiopathy DVT

Management of APS  Standard therapy : Heparin  Warfarin  Antiplatelet agent : beneficial when given for prophylaxis in asymptomatic patients with aPL  Hydroxychloroquine : reduced the size of thrombi and the time thrombosis  Immunosuppressive agents : Corticosteroids and cytotoxic drugs (such as cyclophosphamide) are of no proven utility in patients with the APS

Management of APS  APS with prior thrombosis - Life-long warfarin with INR 2-3  APS with late fetal loss - Combined therapy with aspirin and heparin - Indication 1) medium or high titers of aCL 2) >1 fetal losses after 10 weeks gestation 3) no history of a vascular thrombotic event

Management of APS  APS with multiple embryonic losses - Low dose aspirin and heparin therapy in pregnancy - Indication 1) >2 fetal losses and a structurally normal uterus 2) documentation of euploidy 3) stigmata of thrombosis in the placental specimens

Management of APS In case of treatment failure  IV immunoglobulin : 0.4 g/kg/day for 5 days each month during the next attempted pregnancy  Plasmapheresis : reduction in antibody titers  Interleukin 3 : only experimental studies in animal model  Hydroxychloroquine : reverse platelet activation induced by human IgG APA and reverse thrombogenic properties of APA in mice