SYSTEMIC LUPUS ERYTHEMATOSUS 瑞金医院肾脏科 李晓

Introduction SLE is a chronic, usually life-long, potentially fatal autoimmune disease characterized by inflammation in many different organ systems commonly involved skin and kidney.

Introduction SLE is associated with the production of autoantibodies reactive with nuclear, cytoplasma and cell membrane antigens.

Introduction fatigue anemia fever rashes sun sensitivity alopecia arthritis pericarditis pleurisy vasculitis nephritis central nervous system disease

Introduction F:M=7-10:1 Child-bearing age （ 13 ~ 40 years old） Prevalence in women China 113 per 100,000 USA 50 per 100,000

Etiology Genetics HLA-DRw2 and HLA-DRw3 Virus type C viruses isolated Hormone estrogens (androgens) Environment ultraviolet light Drugs procainamide, alpha-methyldopa, D-penicillamine, quinidine, ...

Pathogenesis The deposition of DNA-anti-DNA immune complexes Antibodies to erythrocytes, granulocytes, lymphocytes, and macrophages

Genetic Environmental 1.Lymphoreticular 1.Infections (viral,bacterial,parasite) 2.Hormonal 2.Drugs 3. Metabolic 3.UV light B cell proliferation (nucleic acids,IC, cellular debris) B cell differentiation Genetic Autoantibody production 1.Anti-lymphocyte 2.Anti-nuclear 3.Other +Antigen Tissue deposition Inflammation

Pathology(1) Hematoxylin bodies These basophilic staining bodies are nuclear debris, often associated with antinuclear antibody, and represent a correlate of the LE cell in vivo.

Pathology(2) The spleen has “union skin lesions”, concentric fibrosis of the walls and surrounding tissues of the central and penicilliary arteries.

Pathology(3) Nonbacterial verrucous endocarditis (Libman-Sacks) consists of vegetations on the heart valves or chordas tendiness

Pathology(4) The renal pathology varies from mild to severe glomerular inflammation and variable interstitial involvement, is usually a mixture of proliferative and membranous changes. Extensive crescent formation and substantial glomerular or interstitial scarring are unfavourable prognostic signs.

WHO classification Class I Normal kidney Class II Minimal or Mesangial lupus nephritis Class III Focal proliferative lupus nephritis <25% Class IV Diffuse proliferative lupus nephritis >50% Class V Membranous lupus nephritis Class VI Sclerosis lesions

Clinical Manifestations SLE is a highly variable disease. At the beginning only a single organ may be involved or many systems may be affected simultaneously. Fever, weakness, fatigability, or weight loss may be the first evidence of illness and are often insidious.

Clinical Manifestations Skin malar rash (the characteristic butter-fly), alopecia, oral ulcers, photosensitivity Arthritis symmetrical, the proximal inter-phalangeal joints of the hands, metacarpo-phalangeal joints, wrists, and knees being most commonly affected. No bony erosion.

Clinical Manifestations Serositis pleuritis or pericarditis Renal disorder proteinuria/ hematuria, nephrotic syndrome, renal insufficiency Heart nonbecterial verrucous endocarditis Lung diffuse interstitial pneumonitis

Clinical Manifestations Liver liver enlargement, liver enzyme elevation Neurologic disorder seizures, psychosis Hematologic problems anemia, thrombo-cytopenia

Laboratory Findings Full blood count hemolytic anemia, leukopenia, thrombocytopenia, ESR Urinalysis hematuria, proteinuria, red and white cell casts

Laboratory Findings Immunological examination 1. LE cell The antibody reacts with whole nuclei, coats the nucleus, and then is phagocytized, leading to the formation of the LE cell.

Laboratory Findings 2. Antinuclear antibodies (ANA) The best screening test for SLE. ANA are found in 95% of patients with SLE, often in high titer. However, ANA may be found occasionally in normals and sometimes in patients with other disorders, but usually in low titer.

Laboratory Findings 3. Anti-ds-DNA antibody High titers of anti-ds-DNA antibodies are seem only in SLE. Radioimmunoassay is used. This test should be carried out on all patients suspected of having SLE. 4.Anti-Sm antibodies Specific for SLE patients.

Laboratory Findings 5. Complement Markedly depressed complement levels including CH50,C4 and C3 are seen primary in patients with active lupus nephritis. The low levels probably reflect in vivo activation and fixation of complement components by CIC.

Laboratory findings Lupus band test (LBT) Studies of nonlesional skin from patients with SLE about 50% of the patients have revealed deposits of immunoglobulin and complement proteins at the dermal-epidermal junction. Renal biopsy is very important for the diagnosis of patients with SLE.

Criteria for Classification of Systemic Lupus Erythematosus (1982) Criterion 1. Malar rash 2. Discoid rash 3. Photo- sensitivity 4.Oral ulcers Definition Fixed erythema, flat or raised, over malar eminences, spare the nasolabial folds. Skin rash as a result of unusual reaction to sunlight Usually painless

two or more peripheral joints, characterized by tenderness swelling Criterion 5.Arthritis 6.Serositis 7.Renal disorder 8.Neurologic disorder Definition Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness swelling or effusion a)Pleuritis OR b)Pericarditis a)Persistent proteinuria >0.5g/d OR b)Cellular casts: red cell, granular, hemoglobin, tubular, or mixed a)Seizures OR b)Psychosis

a)Positive LE cell preparation OR b)Anti-DNA OR c)Anti-Sm OR Criterion 9.Hematologic disorder 10.Immunologic disorder 11.Antinuclear antibody Definition a)Hemolytic anemia OR b)Leukopenia OR c)Lymphopenia OR d)Thrombocytopenia a)Positive LE cell preparation OR b)Anti-DNA OR c)Anti-Sm OR d)False-positive serologic test for syphilis

For the purpose of identifying patients in clinical studies, a person shall be said to have systemic lupus erythematosus if any 4 or more of the 11 criteria are present.

Therapy Patients with SLE usually need more than normal rest. Ultraviolet light should be avoided. Stress, including surgery, infections, childbirth, abortions, and psychological pressures, may exacerbate disease.

Therapy 1. Nonsteroidal anti-inflammatory drugs (NSAID) such as aspirin and ibuprofen are useful for arthritis, serositis, and fever. Indomethacin 25-50mg tid p.o. Side effects Gastrointestinal tract hemorrhage Renal tubular-interstitial lesions

Therapy 2. Antimalarials is effective for skin involve-ment, it also may help treat arthritis and other manifestations Chloroquine 0.25 to 0.5 qd p.o.

Therapy 3. Corticosteroids may be necessary in patients with severe involvement. prednisone 1mg/Kg/ day prednisonelone 800-1000mg qd iv.gtt

Therapy 4. Immunosuppressive drugs Cyclophosphamide (CTX) 0.5-1g/m2 Azathioprine 1-2mg/Kg/day p.o. Cyclosporine A 3-5mg/Kg/day p.o. 5. Chinese medicine 雷公藤多甙片 10-20mg tid p.o.

Steroids Prednisone remain the best effective and rapidly acting immunomodulator therapy. Typical initial treatment pred. 1mg/Kg/day ×4-12 weeks

The toxicities of chronic steroids hypertension osteoporosis diabetes atherosclerosis avascular necrosis Cushingoid appearance insomnia striae agitation risk of infection

Cyclophosphamide CTX is considered the most effective cytotoxic in the management of lupus renal disease. The side effects are less in patients treated with parenteral route of CTX than oral CTX.

The major toxicities of CTX bone marrow suppression with peripheral cytopenias permanent ovarian failure with infertility hemorragic cystitis alopecia liver injury risk of infection theoretic risk of malignancy

RHEUMATOID ARTHRITIS

Introduction RA is a chronic, systemic inflammatory disorder of unknown etiology characterized by the manner in which it involved joints. Progressive joint destruction and deformity leads to variable degrees of incapacitation. F:M=2-3:1 40-60 years old

Etiology Genetic factors HLA-DR4 Infection

Etiology Rheumatoid factors (RF) are antibodies with specificity for antigenic determinates on the Fc portion of human or animal IgG. Currently, the most popular notion that RF arise as antibodies to “altered”autologous IgG.

Ab Ab HLA pathogen

Pathology Synovitis edema, cell proliferation Rheumatoid pannus, a vascular granulation tissue composed of proliferation fibroblasts, numerous small blood vessels, and various numbers of inflammatory cells. Vasculitis a widespread necrotizing arteritis of small and medium sized arteries

Pathology Rheumatoid nodules Characteristic histologic changes in nodules showing granulomatous foci with central zones of cell necrosis, surrounded by a palisade of proliferated mononuclear and peripheral fibrosis and chronic inflammatory cell infitration.

Clinical features The onset of RA is frequently heralded by prodromal symptoms such as fatigue, anorexia, weight loss, weakness and generalized aching and stiffness. *Joint disease * Extraarticular manifestations

Clinical features Joint disease The small joints of the hands, the wrists, knees, and feet are most commonly involved. It usually is bilateral, symmetrical, and polyarticular.

Clinical features Joint disease Morning stiffness Swelling Typical hand deformities Limited joint motion

Clinical features Extraarticular manifestations Rheumatoid nodules Vasculitis Pleuropulmonary manifestations Cardiac manifestations Neuropathy Sjogren’s syndrome

Laboratory findings Anemia of moderate degree ESR  a useful parameter for assessing response to therapy C-reactive protein  RF 70% but not specific CIC  , complements 

Laboratory findings Synovial fluid Radiology Bony decalcification localized to or most marked adjacent to the involved joints and not just degenerative changes Rheumatoid nodules

Proposed 1987 Revised American Rheumatism Association Criteria for Rheumatoid Arthritis Morning stiffness for at least one hour and present for at least six weeks Swelling of three or more joints for at least six weeks Swelling of wrist, metacarpophalangeal or proximal interphalangeal joints for six or more weeks Symmetric joint swelling

Proposed 1987 Revised American Rheumatism Association Criteria for Rheumatooid Arthritis Hand roentgenogram changes typical rheumatoid arthritis that must include erosions or unequivocal bony decalci-fication Rheumatoid nodules serum rheumatoid factor by a method positive in less than 5% of normals

Four or more criteria must be present to diagnose rheumatoid arthritis.

Treatment Relief of pain reduction or suppression of inflammation minimizing undesirable side effects preservation of muscle and joint function return to a desirable and productive life

Treatment Treatment pyramid for RF Experiment drugs Penicillamine, Steroids Antimalarials, Gold salts Asprin, NSAIDs, Analgesics Education, Rest, Exercise, Social service

Treatment Drug therapy Nonsteroidal antiinflammatory drugs (NSAIDs) eg: indomethacin, ibuprofen Side effects

Treatment Drug therapy the slow acting drugs including gold, antimalarials and penicillamine eg: chlorquine, gold salts (auranofin), CTX corticosteroid eg: prednisone

Treatment Physical measures Appropriate and skilled therapy can provide notable benefit for the RA patient. Orthopedic surgery can be preventative or reparative