Focused Issue of This Month Systemic Lupus Erythematosus Sung Hwan Park, MD Department of Rheumatology, The Catholic University of Korea College of Medicine E - mail : rapark@catholic.ac.kr J Korean Med Assoc 2009; 52(7): 645-656 Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies to components of the cell nucleus with diverse clinical manifestations, predominantly in women during reproductive years. SLE is caused by interaction between susceptibility genes and environmental factors, which result in abnormal immune response. SLE is caused by failure in regulating the production of pathogenic autoantibodies and the formation of immune complex. Abnormalities in the immune response regulation display a decreased ability to clear immune complexes and apoptotic cells. Genetic predisposition to SLE involves multiple genes. Genetic variants predisposing to SLE may influence clearance of immune complexes or apoptotic bodies, activation of B cells or T cells, and inflammation related to dendritic cell activation. Environmental factors that predispose to or activate SLE include ultraviolet B light, infection with Epstein-Barr virus, female gender, and exposure to estrogencontaining medications. The diagnosis of SLE is based on characteristic clinical features and autoantibodies. The diagnostic criteria of the American College of Rheumatology (ACR) reflect the major clinical features of the disease (mucocutaneous, articular, serosal, renal, neurologic) and incorporate the associated laboratory findings (hematologic and immunologic). Four or more criteria are required for diagnosis. There is no effective cure for SLE, and complete sustained remissions are rare. The treatment should be tailored based on the clinical manifestations in an individual patient. Conservative therapies for management of non-life-threatening manifestations of SLE comprise NSAIDs, corticosteroids and antimalarials. Treatment of severe organ damage requires immunosuppressive agents. Targeted biologic therapies are under development and appear to be promising. Keywords: SLE; Autoantibody; Autoimmunity; Diagnosis; Treatment 645
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Systemic Lupus Erythematosus Table 1. Frequency of various manifestations of systemic lupus erythematosus at disease onset and during the disease. Manifestaton Onset (%) During(%) Arthralgia 77 85 Constitutional 53 77 Skin 53 78 Arthritis 44 63 Renal 38 74 Raynaud's phenomenon 33 60 Central nervous system 24 54 Vasculitis 23 56 Mucous membranes 21 52 Gastrointestial 18 45 Lymphadenopathy 16 32 Pleurisy 16 30 Pericarditis 13 23 Lung 7 14 Nephritic syndrome 5 11 Azotemia 3 8 Myositis 3 3 Thrombophlebitis 2 6 Myocarditis 1 3 Pancreatitis 1 2 647
Park SH Table 2. The revised criteria for the diagnosis of systemic lupus erythematosus Criterion Definition 1. Malar rash: Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds 2. Discoid rash: Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions 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 physician 5. Arthritis: Nonerosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion 6. Serositis a) Pleuritis: convincing history of pleuritic pain or rubbing heard by a physician or evidence of pleural effusion OR b) Pericarditis: documented by ECG or rub or evidence of pericardial effusion 7. Renal disorder a) Persistent proteinuria > 500 mg per day or > 3 + if quantitation not performed OR b) Cellular casts: may be red cell, haemoglobin, granular, tubular, or mixed 8. Neurologic disorder a) Seizures: in the absence of offending drugs or known meta-bolic derangements; e.g., uremia, ketoacidosis, or electrolyte imbalance OR b) Psychosis: in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance 9. Hematologic disorder a) Hemolytic anemia- with reticulocytosis OR b) Leukopenia: < 4,000/mm 3 total OR c) Lymphopenia: < 1,500/mm 3 on two or more occasions OR d) Thrombocytopenia: < 100,000/mm 3 in the absence of offending drugs 10. Immunologic disorder a) Anti-DNA: antibody to native DNA in abnormal titre OR b) Anti- Sm: presence of antibody to Sm nuclear antigen OR c) Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of lgg or lgm anticardiolipin antibodies, (2) a positive test result for lupus anticoagulant using a standard method, or (3) a false-positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test 11. ANA: Abnormal titer of ANA by immunofluorescence or equivalent assay at any point in time, in the absence of drugs known to be associated with drug-induced lupus syndrome This classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a person must have SLE if any 4 or more of the 11 criteria are present, serially or simultaneously, during any lnterval of observation (1).The modifications to criterion number 10 were made in 1997 (2). 648
Systemic Lupus Erythematosus Table 3. Histologic classification of lupus nephritis according to the International Society of Nephrology/Renal Pathology Society, 2003 WHO Type Class I Class II Class III Class IV Class V Class VI Minimal mesangial lupus nephritis Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence Mesangial proliferative nephritis Purely mesangial hypercellularity of any degree of mesangial matrix expansion by light microscopy, with mesangial immune deposits Few isolated subepthelial of subendothelial deposits, may be visible by immunoflurorescence or electron microscopy, but not by light microscopy. Focal lupus nephritis Active or inactive focal, segmental, of global endocapillary or extracapillary glomerulonephritis involving < 50% of all glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations Diffuse lupus nephritis Active of inactive diffuse, segmental, of global endocapillay of extracapillary glomerulonephritis involving < 50% of all glomeruli, typically with diffuse subendothelial immune deposits, with of without mesangial alterations. This class is subdivided into diffuse segmental(iv-s) lupus nerphritis when of the involved glomeruli have segmental lesions, and diffuse global(iv-g)lupus nephritis when 50% of the involved glomeruli have global lesions. Segmental is defined as a glomerular lesion that involves less than half of the glomerular tuft. This class includes cases with diffuse wire loop deposits, but with little or no glomerular proliferation Membranous lupus nephritis Global or segmental subepithelial immune deposits or their morphologic sequelae by light microscopy and by immunofluorescence or electron microscopy, With or without mesangial alterations Class V nephritis may occur in combination whit class III or class IV, in which case both are diagnosed Class V nephritis may show advanced sclerotic lesions Advanced sclerotic lupus nephritis 90% of glomeruli globally sclerosed without residual activit 649
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Systemic Lupus Erythematosus Table 4. Neuropsychiatric syndromes in systemic lupus erythematosus Central Nervous System Aseptic meningitis Cerebrovascular disease Demyelinating syndrome Headache (including migraine and benign intracranial hypertension) Movement disorder(chorea) Myelopathy Seizure disorder Acute confusional state Anxiety disorder Cognitive dysfunction Mood disorder psychosis Peripheral Nervous System Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barre syndrome) Autonomic disorder Mononeuropathy, single/multiplex Myasthenia gravis Neuropathy, cranial Plexopathy Polyneuropathy 651
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Park SH Table 5. Indications for cytotoxic drug use in systemic lupus erythematosus General Involvement of major organs of extensive involvement of nonmajor organs (i.e.,skin) refractory to first-line agents Failure to respond to or inability to taper corticosteroids to acceptable dose for longterm use Specific Organ Involvement Renal Proliferative or membranous nephritis (nephritic syndrome) Hematologic Severe thrombocytopenia (platelets < 20 X 10 mm 3 / ) Thrombotic thrombocytopenic purpura-like syndrome Severe hemolytic or aplastic anemia, or immune neutropenia not responding to corticosteroids. Pulmonary Lupus pneumonitis or alveolar hemorrhage Cardiac Myocarditis with decreased left ventricular function, pericarditis with impending tamponade Gastrointestinal Abdominal vasculitis Nervous system Transverse myelitis, cerebritis, psychosis refractory to corticosteroids, mononeuritis multiplex, severe peripheral neuropathy 654
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