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8-Guideline for elaborate SLE management.ppt

1. The document provides information about systemic lupus erythematosus (SLE) including its epidemiology, symptoms, organ involvement, diagnostic tests, and disease management. 2. SLE most commonly affects women of childbearing age and has a variety of clinical manifestations involving the skin, joints, kidneys, and other organ systems. 3. Diagnosis involves assessing clinical signs and symptoms along with serological tests like ANA and anti-DNA antibodies. Disease activity and organ involvement help guide treatment approaches.

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1 Guideline for SLE management 高雄長庚醫院風濕過敏免疫科
2 Epidemiology of SLE Prevalence of SLE： In U.S：18-24/100000 black female：7.9-10.5/100000 white female：4/100000 More common in urban than in rural areas Female：male=1.4-5.8：1 (children) 8-13：1 (adult) 2：1 (older) Onset age=65% between 16-55 y/o 20% < 16 y/o 15% > 55 y/o Identical twin：30% first degre relative：5% Annual incidence of new case：6/100000 (low-risk group) 35/100000 (high risk group)
3 Subacute Cutaneous Lupus Erythematosus • Widespread, non-scarring but often photosensitive rash • Annular or papulosquamous morphology • Mild systemic disease common but renal involvement rare • Positive ANA in most patients, but anti-nDNA uncommon • Anti-Ro in two thirds patients • HLA-DR3 present in the majority of patients
4 Symptoms Percentage Fatigue 80-100 Fever >80 Weight loss >60 Arthritis, arthralgia 95 Skin Butterfly rash Photosensitivity Mucous membrane lesion Alopecia Raynaud’s phenomenon Purpura Urticaria >80 >50 <58 27-41 <71 17-30 15 8 Renal Nephrosis 50 18 Castrointestinal 38 Pulmonary Pleruisy Effusion Pneumonia 0.9-98 45 24 29 Cardiac Pericarditis Murmurs ECG changes 46 8-48 23 34-70 Lymphadenopathy 50 Splenomegaly 10-20 Hepatomegaly 25 Central nervous system Functional Psychosis Convulsions 25-75 most 5-52 15-20 Table 61-1. FREQUENCY OF CLINICAL SYMPTOMS IN SLE AT ANY TIME
5 Table 9-3. THE SPECTRUM OF ANAs Chromatin Anti-native DNA Anti-single-stranded DNA Anti-Z DNA Anti-centromere Anti-Ku Anti-HMG proteins Anti-topoisomerase I (Scl-70 antigen) Anti-topoisomerase II Anti-PBC 95K Anti-lamins Nucleolar Components Anti-RNA polymerase I Anti-Th Anti-Us (fibrillarin) Anti-Pm/Scl Anti-NOR-90 Other Cellular Components Anti-unclear pore complexes Anti-centrosomes Anti-midbody Anti-spindle Anti-Mi Anti-Su Nuclear Ribonucleoproteins Anti-U1 RNP Anti-Sm Anti-Ro Anti-La Anti-U2 RNP Anti-U4 U6 RNP Anti-U5 RNP Anti-5S rRNAprotein Cytoplasmic Components Anti-Jo-1 (tRNAhistidyl synthetase) Anti-tRNAalanyl synthetase Anti-tRNAthreonyl synthetase Anti-tRNAglycyl synthetase Anti-signal recognition particle (SRP) Anti-ribosomes
6 Fig 1： Four steps in the indirect immunofluorescence assay (cross-sectional view). Monolayer cells grown on a glass slide (A) are fixed and permeabilized (B) with chemicals such as acetone, methanol, ethanol, or formaldehyde. After a first incubation with patient’s serum containing autoantibodies ©, cells are washed to get rid of unbound antibodies, and the second incubation takes place with fluorescent-labeled anti-buman antibody (D). The slides are again washed, mounted with coverslips, and read on a fluorescence microscope. Nu, nucleoplasm; Cy, cytoplasm.
7 CAUSES OF POSITIVE ANTINUCLEAR ANTIBODIES 1. Rheumatic diseases Systemic lupus erythematosus Polymyositis Sjogren’s syndrome Scleroderma Vasculitis Rheumatoid arthritis 2. Normal, healthy individuals Females > males, prevalence increases with age Relatives of patients with rheumatic diseases ? Pregnant females 3. Drug-induced 4. Hepatic diseases Chronic active hepatitis Primary biliary cirrhosis Alcoholic liver disease 5. Pulmonary diseases Idiopathic pulmonary fibrosis Asbestos-induced fibrosis Primary pulmonary hypertension 6. Chronic infections 7. Maliganncies Lymphoma Leukemia Melanoma Solid tumors (ovary, breast, lung, kidney) 8. Hematologic disorders Idiopathic thrombocytopenic purpura Autoimmune hemolytic anemia 9. Miscellaneous Endocrine disorders (type I diabetes mellitus, Graves’ disease) Neurologic diseases (multiple sclerosis) End-stage renal failure After organ transplantation
8
9 Serological Tests to Aid Diagnosis of SLE Test % positive in SLE ANA 95% Anti-nDNA 60% Anti-nRNP 80% Anti-Sm 20% Anti-Ro 30% Anti-La 10%
10 Main patterns of autoantibody 1. Homogenous：Anti-histone 2. Peripheral：Anti-dsDNA, Anti-lamine 3. Speckled ：A large family of nonhiston antigens -Coarse:Anti-Sm, Anti-U1-nRNP -Fine:Anti-Ro, Anti-La -Distinct speckles varying in number(PBC) Anti-p80-coilin, Anti-p95 4. Nucleolar ：Scleroderma or overlap syndrome DNA topoisomerase:nucleolar speckles PM-Scl:homogenous decorating nucleoli Fibrillarin (U3-RNP):clummy nucleolar NOR-90:nucleolar speckles 5. Centromere ：CREST syndrome, and PBC 6. Cytoplasmic ：ANCA,
11 Positive ANA Nucleoli Raynaud’s phenomenon Scleroderma Diffuse (honogeneous) Anti-nucleoprotein SLE RA Drug LE Histone SLE RA Drug LE Centromere CREST Sdleroderma Peripheral (rim) Anti-dsDNA SLE Negative No disease Lab error Treatment Remission Antigen XS Nephrotic syndrome No specificity UCTD SLE RA Liver disease Mono Any chronic inflammatory disease RNP SLE MCTD RA Scleroderma UCTD Sm SLE RO (SS-A) SLE Sogren’s syndrome PcNA SLE Scl-70 Scleroderma PM/Jo/Ku/Mi PM/DM La SLE Sogren’s syndrome Speckled
12 Tabel 1. CUTANEOUS CHANGES IN LUPUS ERYTHEMATOSUS Speclfic Discold Subacute cutaneous Papulosquamous Annular/polycyclic Neonatal lupus erythematosus Malar dermatitis Nonspeclfic Lesions Bullous Lupus panniculitis Alopecia Vasculitis Urticaria-like vasculitis Livedo reticularis Raynaud’s phenomenon Photosensitivity Oral ulcerations Nail changes Cutaneous mucinosis Rheumatoid nodules
13 Table 61-2. MUSCULOSKELETAL MANIFESTATIONS IN SLE SLE RA Arthralgia Common Common Arthritis Common Deforming Symmetry Yes Yes Joints involved PIP > MCP > wrist > knee MCp > wrist > knee Synovial hypertrophy Rare Common Synovial membrane abnormality Minimal Proliferative Synovial fluid Transudate Exudate Subcutaneous nodules Rare 35% Erosions Very rare Common Morning stiffness Minutes Hours Myalgia Common Common Myositis Rare Uncommon Osteoporosis Variable Common Avascular necrosis 5-50% Uncommon Deforming arthritis Swan neck Ulnar deviation Uncommon 10% 5% Common Common Common MCP, Metacarpophalangeal joint; PIP, proximal interphalangeal joint.
14 Possible causes of leukopenia in SLE • Immune destruction • Marrow suppression • Hypersplenism • Drugs
15 Possible causes of anemia in SLE • Anemia of chronic disease • Auto-immune hemolytic anemia • Hypoplastic anemia • Blood loss due to thrombocytopenia or NSAID use • Hypersplenism • Anemia of renal failure
16 AN APPROACH TO THE MANAGEMENT OF LUPUS THROMBOCYTOPENIA • Confirm diagnosis by examining peripheral smear and bone marrow examination, and determine severity • Rule out drug effects and discontinue all but absolutely essential drugs • Rule out thrombotic throbocytopenic purpura (may be indicated by anemia with pronounced reticulocytosis and fragmented erythrocytes in the peripheral smear) • Rule out infection： viral：HIV, HBV, CMV bacterial：subacute bacterial endocarditis, gram-negative sepsis • Look for evidence of lupus activity in other organs; beware of major organ involvement • Use prednisone 0.25-1.0mg/kg/day for 3-4 weeks if platelets < 50.000/mm3 (unless otherwise indicated for other manifestations of lupus); taper after 3-4 weeks The goal is a stable platelet count > 50.000/mm3 • If prednisone fails or unable to tape, consider danazol (400-800mg/day),-globulin or splenectomy • In patients refractory to these modalities or patients with major organ involvement, use monthly pulses of cyclophosphamide for at least 6 months Fig. 7.14 An approach to the management of lupus thrombocytopenia.
17 Lupus lymphadeenitis (I) • The prevalence of lymphadenopathy range from 12- 59% of lupus patients • The most common sites are cervical (43%), mesenteric (21%), axillary (18%) and inguinal (17%). Unusual sites such as hilar, mediastinal and retroperitoneal were also reported • The pathognomonic pathologic feature of lupus lymphadenitis, the hematoxylin body, was described by Ginzler and Fox in 1940, which stain with periodic acid- Schiff and Feulgen methods, are coalescent amorphic aggregates of deeply basophilic material found within areas of lymph node necrosis. • The hematoxylin bodies are highly specific for SLE, are also found in glomeruli, endocardium and spleen
18 Lupus lymphadeenitis (II) • Other lymph node features include paracortical focl of necrosis marked infiltration by histiocytes, lymphocytes and plasma cells and the preesence of imunoblasts. Neutrophils, eosinophils and granulomata are conspiculously absent. • Both lupus lymphadenitis and KFD are characterized by of histiocytic and immunoblastic infiltrates. A prominent plasma cell component strongly suggests lupus lymphadenitis. When present, hematoxylin bodies are virtually diagnostic of SLE. • The clinical feature, building on these pathologic resemblances, supports a link between KFD and SLE. Perhaps KFD and SLE share a common inclting event, such as exposure to an enviromental or infectious agent, that can produce either disorder. Alternatively, KFD may be an antoimmune-midiated necrotizing lymphadenitis that can remain self-limited or develop into SLE
19 Primary Respiratory System Involvement in Systemic Lupus Erythematosus Upper airway disease Epiglottitis Subglottic stenosis Vocal cord paralysis Laryngeal edema or ulceration Inflammatory mass lesions or nodules Cricoarytenoid arthritis Necrotizing vasculitis Parenchymal disease Acute lupus pneumonitis Alveolar hemorrhage syndrome Chronic lupus pneumonitis or interstitial lung disease Lymphocytic interstitial pneumonia or pseudolymphoma Bronchiolitis obliterans with or without organizing pneumonia Respiratory muscle disease Shrinking lung syndrome Pleural disease Pleuritis with or without effusion Vascular diaease Pulmonary hypertension Pulmonary embolism Acute reversible hypoxemia
20 Pulmonary Involvement In SLE Pleural disease Acute lupus pneumonitis Chronic interstitial lung disease Pulmonary hemorrhage Pulmonary embolism Pulmonary vascular disease Diaphragmatic dysfunction
21 Cardic manifestation of SLE Pericardium ： Pericarditis with or without effusion Cardiac tamponade (rare) Constrictive perlcarditis Myocardium ： Myocarditis Endocardium ： Libman-Sacks endocarditis Coronary artery ： Accelerated atherosclerosis vasculitis
22 Common Clinical and Laboratory Findings in Lupus Nephritis • Disordered fluid and electrolyte balance Nocturia, decreased urinary concentrating capacity, hyperkalemia, renal tubular acidosis • Nephritic syndrome Hematuria, cellular casts; variable bypertension, edema, proteinuria, azotemia • Nephrotic syndrome Frothy urine, edema, proteinuria >3.5g per day, lipiduria (fatty casts, oval fat bodies, doubly refractile fat bodies), hypoalbuminemia, hyperlipidemia • Secondary complications of nephrotic syndrome include volume depletion, prerenal azotemia, venous thrombosis, pulmonary embolism, atherosclerosis, hypogammaglobulinemia • Renal insufficiency Acute, rapidly progressive or chronic renal failure
23 Characteristic Clinicopathologic Correlations in the Major Classes of Lupus Nephritis Normal or minimal disease Mesangial lupus nephritis Clinical：low-grade hematuria, proteinuria, normal renal function Pathology：increased mesangial cells, matrix, and immune complexes; patent glomerular capillary loops Focal proliferative lupus nephritis Clinical：nephritic urine sediment, variable but usually nonnephrotic proteinuria Pathology：segmental proliferation, necrosis, crescents compromising capillary loops in <50% of glomeruli; mesangial and subendothelial immune complex deposits Diffuse proliferative lupus nephritis Clinical ：nephritic urine sediment, nephrotic syndrome, hypertension, variable renal insufficiency Pathology：global proliferation, necrosis in >50% of glomeruli; variable sclerosis, atrophy, and fibrosis; mesangial, subendothelial, and subepithelial immune complex deposits Membranous nephropathy Clinical：nephrotic syndrome Pathology：diffuse capillary loop thickening; subepithelial immune deposits
24 Morphological Classification of Lupus Nephritis (modified WHO Classification) Class Biopsy finding I Normal glomerule II Pure messngial alteration III Focal proliferative glomerulonephritis IV Diffuse proliferative glomerulonephritis V Menbranous glomerulopathy VI Advanced glomerulosclerosis
25 INDICES OF ACTIVITY AND CHRONICITY IN LUPUS NEPHRITIS* Activity Index (Range 0 to 24) Glomerular hypercillularity Leukocyte exudation Karyorrhexis/fibrinoid necrosis Cellular crescents Hyaline thrombi Tubulointerstitial inflammation Chronicity index (Range 0 to 12) Glomerular lesions Glomerular sclerosis Fibrous crescents Tubulointerstitial lesions Tubular atrophy Interstitial fibrosis *Individual lesions are scored 0 to 3+ (absent, mild, moderate, severe). Indices are composite scores for individual lesions in each category of activity or chronicity. Necrosis/karyorrhexis and cellular crescents are weighted by a factor of 2.
26 INDICATIONS FOR RENAL BIOPSY IN LUPUS NEPHRITIS Proteinuria of >1g/day The threshold is conventionally 1-2g/day Less proteinuria does not preclude biopsy if it occurs in the context of major serologic abnormalities, especially hypocomplementemia At the other extreme, the presence of full-bolwn nephrotic and nephritic syndromes may make renal biopsy unnecessary Progressive azotemia Decreasing renal function in associtaion with active urinary sediment is an indication for biopsy in order to assess the extent of crescents and necrosis which would warrant very aggressive therapy Ambiguity or inconsistency of data Lupus nephritis of indeterminate duration, severity and potential responsiveness warrants the establishment of a fresh baseline database including determination of class,activity and chronicity indices Overlapping clinical features Situations where clinical and laboratory data are compatible with different classes of lupus nephritis, for which different approaches to management are warranted Redirection of therapy Partially treated or incompletely responsive lupus nephritis for which a change in therapeutic plan is deemed appropriate
27 SLE and ESRD (1) • 5-22% of SLE patients progress to ESRD requiring H/D • In USA, Iupus nephropathy accounting for 1.4% off all ESRD • Decreased clinical and serological lupus activity following ESRD. Some theories had： 1.Depressed cellular and humoral immunity 2.Lack of mediators produced by the kidney 3.Removal of lupus factors by dialysis itself 4.Nature end point in SLE • Survival of lupus patients on dialysis versus non-SLE dialysis patients：no significant
28 SLE and ESRD (2) • Renal transplant graft survival of lupus versus non-lupus patients：no difference • Lupus patients have slightly better outcome with LR rather than CAD grafts • The transplantation time following dialysis need at least 3 months • Recurrence of transplanted allograft is often similar to histologic or immunofluorescent type as in the origin kidney, but it is a rare event.
29 NEUROPSYCHIATRIC MANIFESTATIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS Central Nervous System Diffuse manifestations (35%-60%) Seizures (15%-35%) Organic brain syndromes Organic amnestic/cognitive dysfunction Dementia Altered consciousness Grand mal Focal Temporal lobe Petit mal Psychiatric Psychosis Organic mood/anxiety syndromes Other Headaches Aseptic meningitis Pseudotumor cerebri Normal pressure hydrocephalus Focal manifestations (10%-35%) Cranial neuropathies Cerebrovascular accidents/strokes Transverse myelltis Movement disorders Peripheral Nervous System Peripheral Neuropathies (10%-20%) Other Sensory polyneuropathy Mononeruitis multiplex Chronic, relapsing polyneruopathy Guillien-Barre syndrome Autonomic noruopathy Myasthenial gravis Eaton-Lambert syndrome
30 PATHOGENETIC MECHANISMS CAUSING NEUROPSYCHIATRIC SYMPTOMS IN SYSTEMIC LUPUS ERYTHEMATOSUS Primary Secondary Autoantibody mediated Antineuronal antibodies Vascular occlusion Immune complex-mediated vasculitis Immune complex-mediated anaphylatoxin release causing leukoagglutination Antiphospholipid antibody-associated hypercoagulability Thrombosis Emboli from cardiac source Cytokine effects Combination of mechanisms Infection Hypertension Uremia Electrolyte imbalances Hypoxia Fever Thyroid disease Thrombotic thrombocytopenic purpura Atherosclerotic strokes Emboli from valvular vegetations Subdural hematoma Cerebral lymphoma Medications Drug overdose Corticosteroids NSAIDs Hydroxychloroquine Azathioprine Fibromyalgia Reactive depression
31 Pathogenesis of Neuropsychiatric Events in Patients with SLE •Primary events Vascular occlusion from immune-complex-mediated or antibody (for example, antiphospholipid) –mediated vasculopathy, vasculitis, leukoagglutination, or thrombosis. Cerebral dysfunction from antibodies to brain tissue† (antineruonal, antiribosomal P protein) or cytokines (interleukin-6, interferon-). •Secondary events Infection (meningitis, abscess, discitis) Cerebrovascular accidents due to accelerated atherosclerosis Hypertensive encephalopathy Metabolic encephalopathy (uremia, electrolyte imbalance, fever, hypoxia) Hypercoagulable state due to the nephrotic syndrome Drugs (glucocorticoids, nonsteroidal anti-inflammatory agents, trimethoprim and sulfamethoxazole, hydroxychloroquine, azathioprine). † Intrathecal production or entrance through a blood-brain barrier disturbed by vascular injury.
32 FREQUENCY OF ABNORMAL LABORATORY TESTS COMMONLY USED IN THE EVALUATION OF NEUROPSYCHIATRIC LUPUS ERYTHEMATOSUS Test Frequency of Abnormal Test Result Range (%) Comment Serologic Antimeuronal antibodies Antineurofilament antibodies Antiribosomal-P antibodies Antiphospholipid antibodies 30-92 58 45-90 45-80 Diffuse manifestations Diffuse manifestations Psychosis/depression Focal manifestations, strokes Cerebrospinal fluid Routine Pleocytosis Increased protein] Low glucose 6-34 22-50 3-8 Rule out infection and NSAID meningitis Nonspecific Rule out infection, transerse myelitis Special Antineuronal antibodies (lgG) Elevated Q albumin Elevated lgG/lgM index Oligoclonal bands (2 bands) 90 8-33 25-66 20-82 Diffuse manifestations, present in 40% with focal manifestations Break in blood-brain barrier Diffuse manifestations Diffuse manifestations
33 Pathologic studies in NPLE Several autopsy series agree on several important points There is no pathognomonic lesion that NPLE causes in the brain that is diagnostically specific like the wire loop lesion observed in lupus nephritis. Active vasculitis is rare, bland vasculopathy (vascular hyalinization, perivascular imflammation, and endothelial proliferation associated with microinfarcts and hemorrhage is the most common pathologic abnormalities seen.) Clinical manifestations may not be readily explained by pathologic findings, some NPLE patients, particularly those with diffuse neuropsychiatric manifestations may have normal or unremarkable brain pathology.
34 Proactive and preventive strategies in addition to lupus therapies(1) • Patients education programs, eliminate patient nonadherence • Monitor vital signs, update physical examination, and have laboratory work done • Adhere to a general conditioning exercise program to minimize osteoporosis and muscle atrophy • Cognitive therapy for lupus “fog”;biofeedback for Raynaud’s phenomenon • Counseling and stress management • Physical and occupational therapy, ergonomic work station evaluation
35 Proactive and preventive strategies in addition to lupus therapies(2) • Aggressive proactive management of blood pressure, blood sugars, serum lipids, and weight. Smoking cessation. • Yearly bone densitometry and osteoporosis prevention measures. • Annual electrocardiogram and chest x-ray • Prompt evaluation of all fevers • Periodic screening with carotid duplex scanning, treadmill, or stress testing; screening for, and prophylactic management of, antiphospholipid antibodies.
36 Therapies for lupus patients with skin lesions(1) • General – Avoid sun: clothing, sunscreens, avoid hot part of day with most UV-B light, camouflage cosmetics – Stop smoking (so antimalarials works better) – Thiazides and sulfonylureals may exacerbate skin disease
37 Therapies for lupus patients with skin lesions(2) • Routine therapy – Topical steroids, intralesional steroids – Hydroxychloroquine – Oral corticosteroids – Dapsone for bullous lesions
38 Therapies for lupus patients with skin lesions(3) • Advanced therapy for resistant causes – Subacute cutaneous lupus: mycophenylate mofetil, retinoids, or cyclosporine – Discoid lesions: chloroquine, clofazimine, thalidomide, or cyclosporine – Lupus profundus: dapsone – Chronic lesions over 50% of body: topical nitrogen mustard, BCNU, or tacrolimus – Vasculitis: may need immunosuppressives
39 Therapy for lupus patients with arthritis (no internal organ involvement) • First line: NSAIDs • Cyclooxygenase-2 specific inhibitors (but may induce thrombotic risk in patients with antiphospholipid antibodies) • Low dose hydroxychloroquine(200mg twice a day)
40 Indications of high dose corticosteroid therapy in lupus patients • Severe lupus nephritis • CNS lupus with severe manifestations • Autoimmune thrombocytopenia with extremely low platelet counts (e.g.<30000/mm3) • Autoimmune hemolytic anemia • Acute pneumonitis caused by SLE. • Others: severe vasculitis with visceral organ involvement, serious complications from serositis (pleuritis, pericarditis, or peritonitis)
41 Life-Threatening Manifestations of SLE: Responses to glucocorticoids(1) • Manifestations often responsive to glucocorticoids – Vasculitis – Severe dermatitis of subacute cutaneous lupus erythematosus or SLE – Polyarthritis – Polyserositis—pericarditis, pleurisy, peritonitis – Myocarditis – Lupus pneumonitis
42 Life-Threatening Manifestations of SLE: Responses to glucocorticoids(2) ~(continue) – Glomerulonephritis—proliferative forms – Hemolytic anemia – Thrombocytopenia – Diffuse CNS syndrome—acute confusional state, demyelinating syndromes, intractable headache – Serious cognitive defects – Myelopathies – Peripheral neuropathies – Lupus crisis—high fever and prostration
43 Life-Threatening Manifestations of SLE: Responses to glucocorticoids(3) • Manifestations not often responsive to glucocorticoids – Thrombosis—includes strokes – Glomerulonephritis—scarred end-stage renal disease, pure membranous glomerulonephritis – Resistant thrombocytopenia or hemolytic anemia—occurs in a minority of patients; consider splenectomy, cytotoxics, danazol, or cyclosporine/neoral therapies – Psychosis related to conditions other than SLE, such as glucocorticoid therapy
44 Therapy for patients with lupus nephritis • Previously untreated patients with active lupus nephritis or severe manifestations ( decreased renal function and /or high- grade proteinuria) – First line: high doses of corticosteroids (about 1mg/kg/day) – Cytotoxic drugs or other immunosuppressive drugs
45 The indications of cytotoxic drugs use in the treatment of lupus nephritis • Active and severe GN despite treatment with high dose prednisone • Responded to corticosteroids but require an unacceptably high dose to maintain a response. • Unacceptable side effects from corticosteroids. • Chronic damage on a renal biopsy and other indicators of a poor prognosis.
46 Systemic therapies for nonorgan- threatening lupus • Nonsteroidal anti-inflammatory drugs • Antimalarials • Thalidomide • Hormonal interventions: dehydroepiandrosterone, testosterone patches, bromocriptine, prolactin • Immunosuppressive therapies: azathioprine, methotrexate, leflunomide
47 The management of organ-threatening lupus • Existing immunosuppressive therapies: cyclophosphamide, mycophenolate mofetil, cyclosporine A, fludarabine, cladribine (2-CDA) • Apheresis • Intravenous immunoglobulin • Various biologic agents: BlyS inhibitor, CTLA-4Ig, LL2IgG • Stem cell transplantation
48 Use of Cytotoxic Drugs in SLE : Azathioprine • requires 6–12 months to work well • 1–3 mg/kg/day(initial dose) • 1–2 mg/kg/day(maintenance dose) • Advantage:probably reduces flares, reduces renal scarring, reduces glucocorticoid dose requirement • Side effects: Bone marrow suppression, leukopenia, infection(herpes zoster), infertility, malignancy, early menopause, hepatic damage, nausea
49 Use of Cytotoxic Drugs in SLE: Cyclophosphamide • requires 2–16 weeks to work well • Initial dose:1-3 mg/kg/day orally or 8–20 mg/kg intravenously once a month plus mesna • Maintenance dose:0.5–2 mg/kg/day orally or 8– 20mg/kg intravenously every 4–12 wks plus mesna • Adverse effects:probably reduces flares, reduces renal scarring, reduces glucocorticoid dose requirement • Adverse effects: marrow suppression, leukopenia, infection, infertility, malignancy, menopause,cystitis,nausea
50 The treatment in lupus patients with autoimmune thrombocytopenia • Splenectomy • Danazol • Immunosuppressive or cytotoxic drugs: azathioprine, cyclophosphamide • Intravenous immunoglobulin(IVIG)
51 Other management principles in the treatment of lupus patients(1) • Thrombosis -Anticoagulation • Recurrent fetal loss with antiphospholipid -Heparin in low dose or low-molecular-weight heparin with or without aspirin -If heparin ineffective or not tolerated, use low-dose aspirin alone -Glucocorticoids plus aspirin in moderate to high dose may be used but is controversial • Thrombocytopenia or hemolytic anemia -Intravenous gamma globulin, splenectomy, danazol, cyclosporine, cytotoxic drugs
52 Other management principles in the treatment of lupus patients(2) • Seizures without other serious manifestations -Anticonvulsants • Behavior disorders or psychosis without other serious manifestations: -Psychoactive drugs, neuroleptics • Pure membranous glomerulonephritis: -Limited trials of immunosuppressives or no specific treatment
53 Other management principles in the treatment of lupus patients(3) • Avoid possible disease triggers-sulfa antibiotics, sun, high estrogen-containing birth control pills,alfalfa sprouts • Prevent atherosclerosis • Prevent osteoporosis • Prevent infection • Prevent progression of renal disease • Prevent clots in patients with antiphospholipid antibodies • Treat fatigue.

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8-Guideline for elaborate SLE management.ppt

  • 1.
  • 2.
    2 Epidemiology of SLE Prevalenceof SLE： In U.S：18-24/100000 black female：7.9-10.5/100000 white female：4/100000 More common in urban than in rural areas Female：male=1.4-5.8：1 (children) 8-13：1 (adult) 2：1 (older) Onset age=65% between 16-55 y/o 20% < 16 y/o 15% > 55 y/o Identical twin：30% first degre relative：5% Annual incidence of new case：6/100000 (low-risk group) 35/100000 (high risk group)
  • 3.
    3 Subacute Cutaneous Lupus Erythematosus •Widespread, non-scarring but often photosensitive rash • Annular or papulosquamous morphology • Mild systemic disease common but renal involvement rare • Positive ANA in most patients, but anti-nDNA uncommon • Anti-Ro in two thirds patients • HLA-DR3 present in the majority of patients
  • 4.
    4 Symptoms Percentage Fatigue 80-100 Fever>80 Weight loss >60 Arthritis, arthralgia 95 Skin Butterfly rash Photosensitivity Mucous membrane lesion Alopecia Raynaud’s phenomenon Purpura Urticaria >80 >50 <58 27-41 <71 17-30 15 8 Renal Nephrosis 50 18 Castrointestinal 38 Pulmonary Pleruisy Effusion Pneumonia 0.9-98 45 24 29 Cardiac Pericarditis Murmurs ECG changes 46 8-48 23 34-70 Lymphadenopathy 50 Splenomegaly 10-20 Hepatomegaly 25 Central nervous system Functional Psychosis Convulsions 25-75 most 5-52 15-20 Table 61-1. FREQUENCY OF CLINICAL SYMPTOMS IN SLE AT ANY TIME
  • 5.
    5 Table 9-3. THESPECTRUM OF ANAs Chromatin Anti-native DNA Anti-single-stranded DNA Anti-Z DNA Anti-centromere Anti-Ku Anti-HMG proteins Anti-topoisomerase I (Scl-70 antigen) Anti-topoisomerase II Anti-PBC 95K Anti-lamins Nucleolar Components Anti-RNA polymerase I Anti-Th Anti-Us (fibrillarin) Anti-Pm/Scl Anti-NOR-90 Other Cellular Components Anti-unclear pore complexes Anti-centrosomes Anti-midbody Anti-spindle Anti-Mi Anti-Su Nuclear Ribonucleoproteins Anti-U1 RNP Anti-Sm Anti-Ro Anti-La Anti-U2 RNP Anti-U4 U6 RNP Anti-U5 RNP Anti-5S rRNAprotein Cytoplasmic Components Anti-Jo-1 (tRNAhistidyl synthetase) Anti-tRNAalanyl synthetase Anti-tRNAthreonyl synthetase Anti-tRNAglycyl synthetase Anti-signal recognition particle (SRP) Anti-ribosomes
  • 6.
    6 Fig 1： Foursteps in the indirect immunofluorescence assay (cross-sectional view). Monolayer cells grown on a glass slide (A) are fixed and permeabilized (B) with chemicals such as acetone, methanol, ethanol, or formaldehyde. After a first incubation with patient’s serum containing autoantibodies ©, cells are washed to get rid of unbound antibodies, and the second incubation takes place with fluorescent-labeled anti-buman antibody (D). The slides are again washed, mounted with coverslips, and read on a fluorescence microscope. Nu, nucleoplasm; Cy, cytoplasm.
  • 7.
    7 CAUSES OF POSITIVEANTINUCLEAR ANTIBODIES 1. Rheumatic diseases Systemic lupus erythematosus Polymyositis Sjogren’s syndrome Scleroderma Vasculitis Rheumatoid arthritis 2. Normal, healthy individuals Females > males, prevalence increases with age Relatives of patients with rheumatic diseases ? Pregnant females 3. Drug-induced 4. Hepatic diseases Chronic active hepatitis Primary biliary cirrhosis Alcoholic liver disease 5. Pulmonary diseases Idiopathic pulmonary fibrosis Asbestos-induced fibrosis Primary pulmonary hypertension 6. Chronic infections 7. Maliganncies Lymphoma Leukemia Melanoma Solid tumors (ovary, breast, lung, kidney) 8. Hematologic disorders Idiopathic thrombocytopenic purpura Autoimmune hemolytic anemia 9. Miscellaneous Endocrine disorders (type I diabetes mellitus, Graves’ disease) Neurologic diseases (multiple sclerosis) End-stage renal failure After organ transplantation
  • 8.
  • 9.
    9 Serological Tests toAid Diagnosis of SLE Test % positive in SLE ANA 95% Anti-nDNA 60% Anti-nRNP 80% Anti-Sm 20% Anti-Ro 30% Anti-La 10%
  • 10.
    10 Main patterns ofautoantibody 1. Homogenous：Anti-histone 2. Peripheral：Anti-dsDNA, Anti-lamine 3. Speckled ：A large family of nonhiston antigens -Coarse:Anti-Sm, Anti-U1-nRNP -Fine:Anti-Ro, Anti-La -Distinct speckles varying in number(PBC) Anti-p80-coilin, Anti-p95 4. Nucleolar ：Scleroderma or overlap syndrome DNA topoisomerase:nucleolar speckles PM-Scl:homogenous decorating nucleoli Fibrillarin (U3-RNP):clummy nucleolar NOR-90:nucleolar speckles 5. Centromere ：CREST syndrome, and PBC 6. Cytoplasmic ：ANCA,
  • 11.
    11 Positive ANA Nucleoli Raynaud’s phenomenon Scleroderma Diffuse (honogeneous) Anti-nucleoprotein SLE RA Drug LE Histone SLE RA DrugLE Centromere CREST Sdleroderma Peripheral (rim) Anti-dsDNA SLE Negative No disease Lab error Treatment Remission Antigen XS Nephrotic syndrome No specificity UCTD SLE RA Liver disease Mono Any chronic inflammatory disease RNP SLE MCTD RA Scleroderma UCTD Sm SLE RO (SS-A) SLE Sogren’s syndrome PcNA SLE Scl-70 Scleroderma PM/Jo/Ku/Mi PM/DM La SLE Sogren’s syndrome Speckled
  • 12.
    12 Tabel 1. CUTANEOUSCHANGES IN LUPUS ERYTHEMATOSUS Speclfic Discold Subacute cutaneous Papulosquamous Annular/polycyclic Neonatal lupus erythematosus Malar dermatitis Nonspeclfic Lesions Bullous Lupus panniculitis Alopecia Vasculitis Urticaria-like vasculitis Livedo reticularis Raynaud’s phenomenon Photosensitivity Oral ulcerations Nail changes Cutaneous mucinosis Rheumatoid nodules
  • 13.
    13 Table 61-2. MUSCULOSKELETALMANIFESTATIONS IN SLE SLE RA Arthralgia Common Common Arthritis Common Deforming Symmetry Yes Yes Joints involved PIP > MCP > wrist > knee MCp > wrist > knee Synovial hypertrophy Rare Common Synovial membrane abnormality Minimal Proliferative Synovial fluid Transudate Exudate Subcutaneous nodules Rare 35% Erosions Very rare Common Morning stiffness Minutes Hours Myalgia Common Common Myositis Rare Uncommon Osteoporosis Variable Common Avascular necrosis 5-50% Uncommon Deforming arthritis Swan neck Ulnar deviation Uncommon 10% 5% Common Common Common MCP, Metacarpophalangeal joint; PIP, proximal interphalangeal joint.
  • 14.
    14 Possible causes ofleukopenia in SLE • Immune destruction • Marrow suppression • Hypersplenism • Drugs
  • 15.
    15 Possible causes ofanemia in SLE • Anemia of chronic disease • Auto-immune hemolytic anemia • Hypoplastic anemia • Blood loss due to thrombocytopenia or NSAID use • Hypersplenism • Anemia of renal failure
  • 16.
    16 AN APPROACH TOTHE MANAGEMENT OF LUPUS THROMBOCYTOPENIA • Confirm diagnosis by examining peripheral smear and bone marrow examination, and determine severity • Rule out drug effects and discontinue all but absolutely essential drugs • Rule out thrombotic throbocytopenic purpura (may be indicated by anemia with pronounced reticulocytosis and fragmented erythrocytes in the peripheral smear) • Rule out infection： viral：HIV, HBV, CMV bacterial：subacute bacterial endocarditis, gram-negative sepsis • Look for evidence of lupus activity in other organs; beware of major organ involvement • Use prednisone 0.25-1.0mg/kg/day for 3-4 weeks if platelets < 50.000/mm3 (unless otherwise indicated for other manifestations of lupus); taper after 3-4 weeks The goal is a stable platelet count > 50.000/mm3 • If prednisone fails or unable to tape, consider danazol (400-800mg/day),-globulin or splenectomy • In patients refractory to these modalities or patients with major organ involvement, use monthly pulses of cyclophosphamide for at least 6 months Fig. 7.14 An approach to the management of lupus thrombocytopenia.
  • 17.
    17 Lupus lymphadeenitis (I) •The prevalence of lymphadenopathy range from 12- 59% of lupus patients • The most common sites are cervical (43%), mesenteric (21%), axillary (18%) and inguinal (17%). Unusual sites such as hilar, mediastinal and retroperitoneal were also reported • The pathognomonic pathologic feature of lupus lymphadenitis, the hematoxylin body, was described by Ginzler and Fox in 1940, which stain with periodic acid- Schiff and Feulgen methods, are coalescent amorphic aggregates of deeply basophilic material found within areas of lymph node necrosis. • The hematoxylin bodies are highly specific for SLE, are also found in glomeruli, endocardium and spleen
  • 18.
    18 Lupus lymphadeenitis (II) •Other lymph node features include paracortical focl of necrosis marked infiltration by histiocytes, lymphocytes and plasma cells and the preesence of imunoblasts. Neutrophils, eosinophils and granulomata are conspiculously absent. • Both lupus lymphadenitis and KFD are characterized by of histiocytic and immunoblastic infiltrates. A prominent plasma cell component strongly suggests lupus lymphadenitis. When present, hematoxylin bodies are virtually diagnostic of SLE. • The clinical feature, building on these pathologic resemblances, supports a link between KFD and SLE. Perhaps KFD and SLE share a common inclting event, such as exposure to an enviromental or infectious agent, that can produce either disorder. Alternatively, KFD may be an antoimmune-midiated necrotizing lymphadenitis that can remain self-limited or develop into SLE
  • 19.
    19 Primary Respiratory SystemInvolvement in Systemic Lupus Erythematosus Upper airway disease Epiglottitis Subglottic stenosis Vocal cord paralysis Laryngeal edema or ulceration Inflammatory mass lesions or nodules Cricoarytenoid arthritis Necrotizing vasculitis Parenchymal disease Acute lupus pneumonitis Alveolar hemorrhage syndrome Chronic lupus pneumonitis or interstitial lung disease Lymphocytic interstitial pneumonia or pseudolymphoma Bronchiolitis obliterans with or without organizing pneumonia Respiratory muscle disease Shrinking lung syndrome Pleural disease Pleuritis with or without effusion Vascular diaease Pulmonary hypertension Pulmonary embolism Acute reversible hypoxemia
  • 20.
    20 Pulmonary Involvement InSLE Pleural disease Acute lupus pneumonitis Chronic interstitial lung disease Pulmonary hemorrhage Pulmonary embolism Pulmonary vascular disease Diaphragmatic dysfunction
  • 21.
    21 Cardic manifestation ofSLE Pericardium ： Pericarditis with or without effusion Cardiac tamponade (rare) Constrictive perlcarditis Myocardium ： Myocarditis Endocardium ： Libman-Sacks endocarditis Coronary artery ： Accelerated atherosclerosis vasculitis
  • 22.
    22 Common Clinical andLaboratory Findings in Lupus Nephritis • Disordered fluid and electrolyte balance Nocturia, decreased urinary concentrating capacity, hyperkalemia, renal tubular acidosis • Nephritic syndrome Hematuria, cellular casts; variable bypertension, edema, proteinuria, azotemia • Nephrotic syndrome Frothy urine, edema, proteinuria >3.5g per day, lipiduria (fatty casts, oval fat bodies, doubly refractile fat bodies), hypoalbuminemia, hyperlipidemia • Secondary complications of nephrotic syndrome include volume depletion, prerenal azotemia, venous thrombosis, pulmonary embolism, atherosclerosis, hypogammaglobulinemia • Renal insufficiency Acute, rapidly progressive or chronic renal failure
  • 23.
    23 Characteristic Clinicopathologic Correlationsin the Major Classes of Lupus Nephritis Normal or minimal disease Mesangial lupus nephritis Clinical：low-grade hematuria, proteinuria, normal renal function Pathology：increased mesangial cells, matrix, and immune complexes; patent glomerular capillary loops Focal proliferative lupus nephritis Clinical：nephritic urine sediment, variable but usually nonnephrotic proteinuria Pathology：segmental proliferation, necrosis, crescents compromising capillary loops in <50% of glomeruli; mesangial and subendothelial immune complex deposits Diffuse proliferative lupus nephritis Clinical ：nephritic urine sediment, nephrotic syndrome, hypertension, variable renal insufficiency Pathology：global proliferation, necrosis in >50% of glomeruli; variable sclerosis, atrophy, and fibrosis; mesangial, subendothelial, and subepithelial immune complex deposits Membranous nephropathy Clinical：nephrotic syndrome Pathology：diffuse capillary loop thickening; subepithelial immune deposits
  • 24.
    24 Morphological Classification ofLupus Nephritis (modified WHO Classification) Class Biopsy finding I Normal glomerule II Pure messngial alteration III Focal proliferative glomerulonephritis IV Diffuse proliferative glomerulonephritis V Menbranous glomerulopathy VI Advanced glomerulosclerosis
  • 25.
    25 INDICES OF ACTIVITYAND CHRONICITY IN LUPUS NEPHRITIS* Activity Index (Range 0 to 24) Glomerular hypercillularity Leukocyte exudation Karyorrhexis/fibrinoid necrosis Cellular crescents Hyaline thrombi Tubulointerstitial inflammation Chronicity index (Range 0 to 12) Glomerular lesions Glomerular sclerosis Fibrous crescents Tubulointerstitial lesions Tubular atrophy Interstitial fibrosis *Individual lesions are scored 0 to 3+ (absent, mild, moderate, severe). Indices are composite scores for individual lesions in each category of activity or chronicity. Necrosis/karyorrhexis and cellular crescents are weighted by a factor of 2.
  • 26.
    26 INDICATIONS FOR RENALBIOPSY IN LUPUS NEPHRITIS Proteinuria of >1g/day The threshold is conventionally 1-2g/day Less proteinuria does not preclude biopsy if it occurs in the context of major serologic abnormalities, especially hypocomplementemia At the other extreme, the presence of full-bolwn nephrotic and nephritic syndromes may make renal biopsy unnecessary Progressive azotemia Decreasing renal function in associtaion with active urinary sediment is an indication for biopsy in order to assess the extent of crescents and necrosis which would warrant very aggressive therapy Ambiguity or inconsistency of data Lupus nephritis of indeterminate duration, severity and potential responsiveness warrants the establishment of a fresh baseline database including determination of class,activity and chronicity indices Overlapping clinical features Situations where clinical and laboratory data are compatible with different classes of lupus nephritis, for which different approaches to management are warranted Redirection of therapy Partially treated or incompletely responsive lupus nephritis for which a change in therapeutic plan is deemed appropriate
  • 27.
    27 SLE and ESRD(1) • 5-22% of SLE patients progress to ESRD requiring H/D • In USA, Iupus nephropathy accounting for 1.4% off all ESRD • Decreased clinical and serological lupus activity following ESRD. Some theories had： 1.Depressed cellular and humoral immunity 2.Lack of mediators produced by the kidney 3.Removal of lupus factors by dialysis itself 4.Nature end point in SLE • Survival of lupus patients on dialysis versus non-SLE dialysis patients：no significant
  • 28.
    28 SLE and ESRD(2) • Renal transplant graft survival of lupus versus non-lupus patients：no difference • Lupus patients have slightly better outcome with LR rather than CAD grafts • The transplantation time following dialysis need at least 3 months • Recurrence of transplanted allograft is often similar to histologic or immunofluorescent type as in the origin kidney, but it is a rare event.
  • 29.
    29 NEUROPSYCHIATRIC MANIFESTATIONS INSYSTEMIC LUPUS ERYTHEMATOSUS Central Nervous System Diffuse manifestations (35%-60%) Seizures (15%-35%) Organic brain syndromes Organic amnestic/cognitive dysfunction Dementia Altered consciousness Grand mal Focal Temporal lobe Petit mal Psychiatric Psychosis Organic mood/anxiety syndromes Other Headaches Aseptic meningitis Pseudotumor cerebri Normal pressure hydrocephalus Focal manifestations (10%-35%) Cranial neuropathies Cerebrovascular accidents/strokes Transverse myelltis Movement disorders Peripheral Nervous System Peripheral Neuropathies (10%-20%) Other Sensory polyneuropathy Mononeruitis multiplex Chronic, relapsing polyneruopathy Guillien-Barre syndrome Autonomic noruopathy Myasthenial gravis Eaton-Lambert syndrome
  • 30.
    30 PATHOGENETIC MECHANISMS CAUSINGNEUROPSYCHIATRIC SYMPTOMS IN SYSTEMIC LUPUS ERYTHEMATOSUS Primary Secondary Autoantibody mediated Antineuronal antibodies Vascular occlusion Immune complex-mediated vasculitis Immune complex-mediated anaphylatoxin release causing leukoagglutination Antiphospholipid antibody-associated hypercoagulability Thrombosis Emboli from cardiac source Cytokine effects Combination of mechanisms Infection Hypertension Uremia Electrolyte imbalances Hypoxia Fever Thyroid disease Thrombotic thrombocytopenic purpura Atherosclerotic strokes Emboli from valvular vegetations Subdural hematoma Cerebral lymphoma Medications Drug overdose Corticosteroids NSAIDs Hydroxychloroquine Azathioprine Fibromyalgia Reactive depression
  • 31.
    31 Pathogenesis of NeuropsychiatricEvents in Patients with SLE •Primary events Vascular occlusion from immune-complex-mediated or antibody (for example, antiphospholipid) –mediated vasculopathy, vasculitis, leukoagglutination, or thrombosis. Cerebral dysfunction from antibodies to brain tissue† (antineruonal, antiribosomal P protein) or cytokines (interleukin-6, interferon-). •Secondary events Infection (meningitis, abscess, discitis) Cerebrovascular accidents due to accelerated atherosclerosis Hypertensive encephalopathy Metabolic encephalopathy (uremia, electrolyte imbalance, fever, hypoxia) Hypercoagulable state due to the nephrotic syndrome Drugs (glucocorticoids, nonsteroidal anti-inflammatory agents, trimethoprim and sulfamethoxazole, hydroxychloroquine, azathioprine). † Intrathecal production or entrance through a blood-brain barrier disturbed by vascular injury.
  • 32.
    32 FREQUENCY OF ABNORMALLABORATORY TESTS COMMONLY USED IN THE EVALUATION OF NEUROPSYCHIATRIC LUPUS ERYTHEMATOSUS Test Frequency of Abnormal Test Result Range (%) Comment Serologic Antimeuronal antibodies Antineurofilament antibodies Antiribosomal-P antibodies Antiphospholipid antibodies 30-92 58 45-90 45-80 Diffuse manifestations Diffuse manifestations Psychosis/depression Focal manifestations, strokes Cerebrospinal fluid Routine Pleocytosis Increased protein] Low glucose 6-34 22-50 3-8 Rule out infection and NSAID meningitis Nonspecific Rule out infection, transerse myelitis Special Antineuronal antibodies (lgG) Elevated Q albumin Elevated lgG/lgM index Oligoclonal bands (2 bands) 90 8-33 25-66 20-82 Diffuse manifestations, present in 40% with focal manifestations Break in blood-brain barrier Diffuse manifestations Diffuse manifestations
  • 33.
    33 Pathologic studies inNPLE Several autopsy series agree on several important points There is no pathognomonic lesion that NPLE causes in the brain that is diagnostically specific like the wire loop lesion observed in lupus nephritis. Active vasculitis is rare, bland vasculopathy (vascular hyalinization, perivascular imflammation, and endothelial proliferation associated with microinfarcts and hemorrhage is the most common pathologic abnormalities seen.) Clinical manifestations may not be readily explained by pathologic findings, some NPLE patients, particularly those with diffuse neuropsychiatric manifestations may have normal or unremarkable brain pathology.
  • 34.
    34 Proactive and preventivestrategies in addition to lupus therapies(1) • Patients education programs, eliminate patient nonadherence • Monitor vital signs, update physical examination, and have laboratory work done • Adhere to a general conditioning exercise program to minimize osteoporosis and muscle atrophy • Cognitive therapy for lupus “fog”;biofeedback for Raynaud’s phenomenon • Counseling and stress management • Physical and occupational therapy, ergonomic work station evaluation
  • 35.
    35 Proactive and preventivestrategies in addition to lupus therapies(2) • Aggressive proactive management of blood pressure, blood sugars, serum lipids, and weight. Smoking cessation. • Yearly bone densitometry and osteoporosis prevention measures. • Annual electrocardiogram and chest x-ray • Prompt evaluation of all fevers • Periodic screening with carotid duplex scanning, treadmill, or stress testing; screening for, and prophylactic management of, antiphospholipid antibodies.
  • 36.
    36 Therapies for lupuspatients with skin lesions(1) • General – Avoid sun: clothing, sunscreens, avoid hot part of day with most UV-B light, camouflage cosmetics – Stop smoking (so antimalarials works better) – Thiazides and sulfonylureals may exacerbate skin disease
  • 37.
    37 Therapies for lupuspatients with skin lesions(2) • Routine therapy – Topical steroids, intralesional steroids – Hydroxychloroquine – Oral corticosteroids – Dapsone for bullous lesions
  • 38.
    38 Therapies for lupuspatients with skin lesions(3) • Advanced therapy for resistant causes – Subacute cutaneous lupus: mycophenylate mofetil, retinoids, or cyclosporine – Discoid lesions: chloroquine, clofazimine, thalidomide, or cyclosporine – Lupus profundus: dapsone – Chronic lesions over 50% of body: topical nitrogen mustard, BCNU, or tacrolimus – Vasculitis: may need immunosuppressives
  • 39.
    39 Therapy for lupuspatients with arthritis (no internal organ involvement) • First line: NSAIDs • Cyclooxygenase-2 specific inhibitors (but may induce thrombotic risk in patients with antiphospholipid antibodies) • Low dose hydroxychloroquine(200mg twice a day)
  • 40.
    40 Indications of highdose corticosteroid therapy in lupus patients • Severe lupus nephritis • CNS lupus with severe manifestations • Autoimmune thrombocytopenia with extremely low platelet counts (e.g.<30000/mm3) • Autoimmune hemolytic anemia • Acute pneumonitis caused by SLE. • Others: severe vasculitis with visceral organ involvement, serious complications from serositis (pleuritis, pericarditis, or peritonitis)
  • 41.
    41 Life-Threatening Manifestations ofSLE: Responses to glucocorticoids(1) • Manifestations often responsive to glucocorticoids – Vasculitis – Severe dermatitis of subacute cutaneous lupus erythematosus or SLE – Polyarthritis – Polyserositis—pericarditis, pleurisy, peritonitis – Myocarditis – Lupus pneumonitis
  • 42.
    42 Life-Threatening Manifestations ofSLE: Responses to glucocorticoids(2) ~(continue) – Glomerulonephritis—proliferative forms – Hemolytic anemia – Thrombocytopenia – Diffuse CNS syndrome—acute confusional state, demyelinating syndromes, intractable headache – Serious cognitive defects – Myelopathies – Peripheral neuropathies – Lupus crisis—high fever and prostration
  • 43.
    43 Life-Threatening Manifestations ofSLE: Responses to glucocorticoids(3) • Manifestations not often responsive to glucocorticoids – Thrombosis—includes strokes – Glomerulonephritis—scarred end-stage renal disease, pure membranous glomerulonephritis – Resistant thrombocytopenia or hemolytic anemia—occurs in a minority of patients; consider splenectomy, cytotoxics, danazol, or cyclosporine/neoral therapies – Psychosis related to conditions other than SLE, such as glucocorticoid therapy
  • 44.
    44 Therapy for patientswith lupus nephritis • Previously untreated patients with active lupus nephritis or severe manifestations ( decreased renal function and /or high- grade proteinuria) – First line: high doses of corticosteroids (about 1mg/kg/day) – Cytotoxic drugs or other immunosuppressive drugs
  • 45.
    45 The indications ofcytotoxic drugs use in the treatment of lupus nephritis • Active and severe GN despite treatment with high dose prednisone • Responded to corticosteroids but require an unacceptably high dose to maintain a response. • Unacceptable side effects from corticosteroids. • Chronic damage on a renal biopsy and other indicators of a poor prognosis.
  • 46.
    46 Systemic therapies fornonorgan- threatening lupus • Nonsteroidal anti-inflammatory drugs • Antimalarials • Thalidomide • Hormonal interventions: dehydroepiandrosterone, testosterone patches, bromocriptine, prolactin • Immunosuppressive therapies: azathioprine, methotrexate, leflunomide
  • 47.
    47 The management oforgan-threatening lupus • Existing immunosuppressive therapies: cyclophosphamide, mycophenolate mofetil, cyclosporine A, fludarabine, cladribine (2-CDA) • Apheresis • Intravenous immunoglobulin • Various biologic agents: BlyS inhibitor, CTLA-4Ig, LL2IgG • Stem cell transplantation
  • 48.
    48 Use of CytotoxicDrugs in SLE : Azathioprine • requires 6–12 months to work well • 1–3 mg/kg/day(initial dose) • 1–2 mg/kg/day(maintenance dose) • Advantage:probably reduces flares, reduces renal scarring, reduces glucocorticoid dose requirement • Side effects: Bone marrow suppression, leukopenia, infection(herpes zoster), infertility, malignancy, early menopause, hepatic damage, nausea
  • 49.
    49 Use of CytotoxicDrugs in SLE: Cyclophosphamide • requires 2–16 weeks to work well • Initial dose:1-3 mg/kg/day orally or 8–20 mg/kg intravenously once a month plus mesna • Maintenance dose:0.5–2 mg/kg/day orally or 8– 20mg/kg intravenously every 4–12 wks plus mesna • Adverse effects:probably reduces flares, reduces renal scarring, reduces glucocorticoid dose requirement • Adverse effects: marrow suppression, leukopenia, infection, infertility, malignancy, menopause,cystitis,nausea
  • 50.
    50 The treatment inlupus patients with autoimmune thrombocytopenia • Splenectomy • Danazol • Immunosuppressive or cytotoxic drugs: azathioprine, cyclophosphamide • Intravenous immunoglobulin(IVIG)
  • 51.
    51 Other management principlesin the treatment of lupus patients(1) • Thrombosis -Anticoagulation • Recurrent fetal loss with antiphospholipid -Heparin in low dose or low-molecular-weight heparin with or without aspirin -If heparin ineffective or not tolerated, use low-dose aspirin alone -Glucocorticoids plus aspirin in moderate to high dose may be used but is controversial • Thrombocytopenia or hemolytic anemia -Intravenous gamma globulin, splenectomy, danazol, cyclosporine, cytotoxic drugs
  • 52.
    52 Other management principlesin the treatment of lupus patients(2) • Seizures without other serious manifestations -Anticonvulsants • Behavior disorders or psychosis without other serious manifestations: -Psychoactive drugs, neuroleptics • Pure membranous glomerulonephritis: -Limited trials of immunosuppressives or no specific treatment
  • 53.
    53 Other management principlesin the treatment of lupus patients(3) • Avoid possible disease triggers-sulfa antibiotics, sun, high estrogen-containing birth control pills,alfalfa sprouts • Prevent atherosclerosis • Prevent osteoporosis • Prevent infection • Prevent progression of renal disease • Prevent clots in patients with antiphospholipid antibodies • Treat fatigue.