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Systemic Lupus Erythematosus

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1 Systemic Lupus Erythematosus

2 INTRODUCTION Systemic Lupus erythematosus ( SLE ) is a syndrome of unknown aetiology most commonly affecting young women. Virtually any organ of the body may be involved Typically the course of the disease is a series of remissions and exacerbations. With good management, the ten years survival may be over 90%.

3 Etiology and Pathogenesis of SLE

4 1. Genetic factor Many studies have described familial aggregation of SLE % of lupus have at least one first or second degree relative with lupus It was found a 24-58% concordance in monozygotic twins. 2-5% concordance in dizygotic twins or siblings. The risk of a child developing lupus born from a mother (or father) with lupus is calculated to be 3-4% at worst.

5 What are the reasons of Genetic susceptibility?
It seems likely that most of the genes predisposing to SLE are normal. An individual inherits an unlucky combination of normal genetic polymorphisms, each of which permit a little immune overreponse, or presentation of high quantities of target antigens in certain tissues. The combination of which is just enough to permit SLE to evolve after some environmental stimulus. C2, C4, C1q deficiencies, DR2, DR3, 1q41-42 region, Fc-r RIIA, IL10 and Bcl polymorphisms.

6 2. Environmental factors
UV light, especially UVB, flares SLE in most patients. It is unclear whether exposure to UV light can initiate the lupus, but onset after a sunburn is not unusual. There is good evidence that exposure of skin to UV light alters the location and chemistry of DNA as well as the availability of Ro and RNP antigens. Drug-induced lupus. Drugs ( hydralazine, procainamide, beta-blokers, isoniazid, penicillamine) can induce lupus. Drug-induce lupus may resemble SLE both clinically and serologically. Usually the disease is mild, and renal and neurological complications are rare. Generally, lupus that is caused by a drug exposure goes away once the drug is stopped.

7 Allergy. Does it induce lupus flare? No direct evidence.
Infection. There has been continuing interest in the possibility that infectious agents might initiate or flare SLE. Mechanism might include molecular mimicry between external Ag and a self-Ag, epitope spreading, nonspecific activation of T or B cells. There has been recent interest in EB, CMV and other virus.

8 3. Sex hormones Female : Male=9:1
The sex difference is most prominent during the female reproductive years. In mice, castrating females and /or providing androgens or antiestrogens protects from disease,whereas castrating males and providing estrogens accelerates and worsens SLE.

9 The metabolish of sex hormone is abnormal in some lupus patients
The metabolish of sex hormone is abnormal in some lupus patients. Men and women with lupus metabolized testosterone more rapidly than normal, and estrogenic metabolites of estradial persist longer in women. Neuroendocrine system. Hyperprolactinemia, abnormalities in hypothalamic and/or pituitary function.

10 4. Abnormal immune system
Sustained presence of autoantigens: increased apoptosis , impaired clearance of apoptosis Hyperactivity in B and T lymphocyte. Increased expression of surface molecules participating in cell activation in both B- and T-cell. Overproduction of IL-6 and IL-10 Defective regulatory mechanism.

11 Autoimmine Diseases Autoimmune diseases result from a break down of self tolerance

12 Autoantibodies to DNA, RNA, and a host of other cell nucleus antigens.
Circulating immune complexes are frequently observed and these may deposit in the kidney, skin, brain, lung, and other tissues. It causes inflammation and tissue damage by a number of mechanism, notably fixation and activation of the complement system.

13 Overview of the pathogenesis of SLE
Infection UV light Self Ag External Ag Skin cell APC Genetic susceptibility T cell T cell IC APC B cell Target Ab Defective IC clearance

14 SLE Tissue damage occurs by:
1. The formation of immune complexes (type III hypersensitivity) 2. Antibody mediated injury to blood cells (type II hypersensitivity) The mere presence of the autoantibodies seen in these disorders can not be the sole cause of these disorders as the antigens for all these antibodies should normally be sequestered inside cells and not exposed the antibodies in the extracellular environment.

15 Clinical manifestations of SLE

16 In systemic lupus erythematosus all pathways lead to endogenous nucleic acids-mediated production of interferon (IFNα). In systemic lupus erythematosus all pathways lead to endogenous nucleic acids-mediated production of interferon (IFNα). Increased production of auto-antigens during apoptosis (ultraviolet (UV)-related and/or spontaneous), decreased disposal, deregulated handling and presentation, are all important for the initiation of the autoimmune response. Nucleosomes containing endogenous danger ligands that can bind to pathogen-associated molecular pattern receptors are incorporated in apoptotic blebs that promote the activation of dendrite cells (DC) and B cells and the production of IFNα and autoantibodies, respectively. Cell surface receptors such as the BCR and Fcγ receptor RIIa facilitate the endocytosis of nucleic acid containing material or immune complexes and the binding to endosomal receptors of the innate immunity such as Toll-like receptors (TLR). At the early stages of disease, when autoantibodies and immune complexes may not have been formed, antimicrobial peptides released by damaged tissues such as LL37 and neutrophil extracellular traps, may bind with nucleic acids inhibiting their degradation and thus facilitating their endocytosis and stimulation of TLR-7/9 in plasmacytoid DC. Increased amounts of apoptosis-related endogenous nucleic acids stimulate the production of IFNα and promote autoimmunity by breaking self-tolerance through activation of conventional (myeloid) DC. Production of autoantibodies by B cells in lupus is driven by the availability of endogenous antigens and is largely dependent upon T-cell help, mediated by cell surface interactions (CD40L/CD40) and cytokines (IL-21). Chromatin-containing immune complexes vigorously stimulate B cells due to combined BCR/TLR crosslinking. Bertsias G K et al. Ann Rheum Dis 2010;69: ©2010 by BMJ Publishing Group Ltd and European League Against Rheumatism

17 Clinical manifestations of SLE

18 The clinical spectrum of SLE is very broad
It make SLE both fascinating but potentially difficult to diagnose and manage.

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21 Disease course of systemic lupus erythematosus (SLE).
Disease course of systemic lupus erythematosus (SLE). SLE starts with a preclinical phase characterised by autoantibodies common to other systemic autoimmune diseases and proceeds with a more disease-specific clinically overt autoimmune phase. It is a disease of variable severity with time periods of flares intercepting periods of remission that culminates in disease and therapy-related damage, such as alopecia, fixed erythema, cognitive dysfunction, valvular heart disease, avascular necrosis, tendon rupture, Jaccoud's arthropathy and osteoporosis. Early damage is mostly related to disease, whereas late damage, namely infections, atherosclerosis and malignancies, is usually related to complications of long-standing disease and immunosuppressive therapy. SLICC, Systemic Lupus International Collaborating Clinics; UV, ultraviolet. Bertsias G K et al. Ann Rheum Dis 2010;69: ©2010 by BMJ Publishing Group Ltd and European League Against Rheumatism

22 General symptoms The most common symptoms listed as initial complaints are fatigue, fever, and weight loss. Fever: fever secondary to active disease was recorded from 50% to 86%. No fever curve or pattern is characteristic. It can be difficult, but very important to distinguish the fever of SLE from that caused by complicating infections.

23 Fatigue is common in patients with SLE, especially during periods of disease activity. It is also often the only symptom that remains after treatment of acute flares. Low grade fever, anemia, or any source of inflammation can result in fatigue.

24 Raynaud’s phenomenon is commonly found in lupus. It lack specificity.
(a triphasic reaction of distal digits to cold or emotion, in which the skin colour changes from white to blue to red)

25 Dermatological involvement
Up to 85% of SLE Butterfly rash Maculopapular eruption Discoid lupus Relapsing nodular non-suppurative panniculitis Vasculitic skin lesin Livedo reticularis Purpuric lesions Alopecia Oral ulcer

26 Photosensitivity sun poisoning rash

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28  Skin clinical and pathology changes: a typical lupus skin rash seen in July 2003 (A) and in September 2003 (B).  Skin clinical and pathology changes: a typical lupus skin rash seen in July 2003 (A) and in September 2003 (B). Skin biopsy in November 2000 (face) showing signs of discoid lupus (C) and in July 2003 (arm) showing signs of subacute lupus (D). Gensburger D et al. Ann Rheum Dis 2005;64: ©2005 by BMJ Publishing Group Ltd and European League Against Rheumatism

29 Malar rash: This is a "butterfly-shaped" red rash over the cheeks below the eyes and across the bridge of the nose. It may be a flat or a raised rash. The rashes are made worse by sun exposure.

30 Maculopapular eruption

31 Discoid lupus These are red, raised patches with scaling of the overlying skin.

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42 Seal’s facial scars are the result of discoid lupus

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45 SLE Drug induced lupus has been seen with hydralizine, procainamide, isoniazid and D-penicillamine*; all usually remit when the offending drug is discontinued.

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47 Vasculitic skin lesin

48 Alopecia

49 Oral ulcer: Painless sores in the nose or mouth need to be observed and documented by a doctor.

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51 Ulcerated leukocytoclastic vasculitis in SLE

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53 53 yo BF with severe generalized weakness,
weight loss, and chronic psychosis Alopecia Psychosis Malar rash Arthritis

54 Musculoskeletal system
The arthritis of lupus is usually found on both sides of the body and does not cause deformity of the joints. Swelling and tenderness must be present. The most frequently involved joints are those of the hand, knees, and wrists. People with lupus can suffer from a certain type of low blood flow injury to a joint causing death of the bone in the joint. The muscle involvement was reported in 30-50% of lupus patients

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56 Avacular necrosis of bone.
It may be caused by prednisone therapy

57 Kidney system Haematuria Proteinure (>0.5g protein/d or 3+ ) Cast

58 Nervous system The brain , nerve problems and psychiatric syndromes are common in lupus affecting up to two-thirds of people. Potential disorders include seizures, nerve paralysis, severe depression, and even psychosis. Spinal cord involvement in lupus is rare and occurs primarily when there is clot formation in a critical vessel that supplies blood to the spinal cord.

59 Hematological abnormalities
Red blood cells a normochromic, normocytic anemia is frequently found in SLE. They appears to be related to chronic inflammation, drug-related haemorrhage. haemolytic anemia as detected by the Coombs’ test is the feature of SLE. on rare occasion, a serum antibody may be produced which impairs red cell production.

60 Platelets. thrombocytopenia (<100*109/L) appears to be mediated by anti-platelet antibodies or/and anti-phospholipid antibodies.

61 White blood cell leucopenia (<4.0*109/L), its cause is probably a combination of destruction of white cells by autoantibodies, decreased marrow production, increased or marginal splenic pooling, and complement activation. it should also noted that the immunosuppressive drugs used in the treatment of SLE may cause a marked leucopenia.

62 Pulmonary manifestations
Pleurisy it is the most common manifestation of pulmonary involvement of SLE. The volume of pleural effusions usually is small to moderate and maybe unilateral or bilateral. Large pleural effusion are uncommon. It usually exudative in character. Pleural effusions may also occur in SLE patients with nephrotic syndrome, infection, cardiac failure.

63 Lung 1) acute lupus pneumonitis: fever, dyspnea, cough with scanty sputum, hemoptysis, tachypnea and pleuritic chest pain. 2) pulmonary hemorrhage 3) chronic diffuse interstitial lung disease. the diagnosis should not be made until infectious processes such as viral pneumonia, tuberculosis, and other bacterial, fungal and pneumocystis carinii infection have been completely excluded.

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66 Cardiovascular manifestations
Pericarditis is the most common cardiac manifestation of SLE. Myocarditis (the clinical features of lupus myocarditis resembles that of viral myocarditis) Libman-Sacks endocarditis and valvular disease Hypertension, cardiac failure

67 Pericarditis

68 SLE can be associated with endocarditis
SLE can be associated with endocarditis. Shown here is Libman-Sacks endocarditis in which there are many flat, reddish-tan vegetations spreading over the mitral valve and chordae. Transesophageal image of a mitral valve with masses characteristic of Libman-Sacks endocarditis.

69 Gastrointestinal and hepatic manifestation
Esophagitis, dysphagia, nausea, vomiting: (drug related in most cases) Chronic intestinal pseudo-obstruction, mesenteric vasculitis, protein-losing enteropathy Pancreatitis Lupus hepatitis

70 Eyes The eyes are rarely involved in lupus except for the retina. People with lupus often have to be screened by an ophthalmologist if they are taking the antimalarial drugs chloroquine or hydroxychloroquine

71 Secondary sjogren’s syndrome
Dry eyes Dry mouth exocrine glands were infiltrated with lymphocytes

72 Secondary Antiphospholipid syndrome
Antiphospholipid syndrome (APS) is characterized by recurrent arterial and /or venous thrombosis, fetal loss and thrombocytopenia. High titer of Antiphospholipid antibody can be found in APS patients.

73 (A) Cutaneous necrosis of the legs.
(A) Cutaneous necrosis of the legs. (B) Maximal extension of the skin ulceration, now completely covered by skin autografts. Fiehn C et al. Ann Rheum Dis 2001;60: ©2001 by BMJ Publishing Group Ltd and European League Against Rheumatism

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75 Deep venous thrombosis (blood clot)
Deep venous thrombosis (blood clot). Notice the contrast between the involved left leg and the normal right leg. Redness, swelling, and warmth combined with discomfort in the involved leg are cardinal manifestations of a deep venous thrombosis.

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78 Laboratory investigation

79 Autoantibodies in SLE Antibodies to cell nucleus component
ANA, anti-dsDNA, antibodies to extracellular nuclear antigen (ENA, anti-Sm, anti-RNP, anti-Jo1) Antibodies to cytoplasmic antigens anti-SSA, anti-SSB Cell-specific autoantibodies lymphocytotoxic antibodies, anti-neurone antibodies, anti-erythrocyte antibodies, anti-platelet antibodies Antibodies to serum components antiphospholipid antibody anticoagulants antiglobulin (rheumatoid factor)

80 Anti-nuclear antibodies
The lupus erythematosus (LE) cell it has been superseded by the ANA and anti-dsDNA techniques. ANA is a screening test anti-Sm, anti-dsDNA antibodies are lupus specific antoantibodies.

81 This homogenous pattern of diffuse bright green staining of nuclei seen by immunofluorescence microscopy with a Hep2 cell substrate is called homogenous, and is the most common pattern with autoimmune diseases overall.

82 This rim (peripheral ) pattern of linear bright green staining around the peripheral of nuclei seen by immunofluorescence microscopy with a Hep2 cell substrate . dsDNA

83 Nucleolar pattern

84 Speckled pattern Scl70, SSA, SSB, Sm

85 These little Crithidia organisms have a small kinetoplast between the nucleus and the flagella which glows bright green under immunofluorescence microscopy, and is indicative of anti-native DNA antibody that is very specific for SLE.

86 Immu-blotting method to detect anti-Sm, RNP, SSA, SSB, Jo1, Scl70 and ribosomal P.

87 Antibodies in SLE Antinuclear Antibody (ANA)
Anti-Native DNA Antibody (Anti-nDNA) Anti-Smith (Anti-Sm) Anti-Ribonucleoprotein Antibody (Anti-RNP) Anti-RO/SSA; Anti-LA/SSB

88 Antinuclear Antibody (ANA)
Most useful in SLE Sensitive but not specific for SLE Also seen in drug-induced lupus, RA, scleroderma, chronic hepatitis Since non-specific for SLE other more specific antibodies were sought

89 ANA: peripheral pattern
If ANA titer is > 1:160, and there is a peripheral pattern, it strongly suggests SLE

90 Anti-nDNA Antibody specific More specific than ANA
Antibodies to “native” double-stranded DNA, a specific nuclear constituent that functions as an autoantigen Occurs in ~70% of patients with SLE Is for SLE specific

91 Anti-nDNA Antibody Used to confirm SLE in someone suspected of having SLE who has a positive ANA Virtually all patients with a positive Anti-nDNA antibody have a positive ANA Therefore, don’t order if patient has a negative ANA

92 Anti-Sm Antibody Specific for SLE Antibody to Smith (Sm) antigen
Present in only 30% of patients with SLE (therefore not sensitive for SLE)

93 Lupus band test Immunofluorescence of skin with antibody to IgG demonstrates a band-like deposition of immune complexes that is bright green at the dermal epidermal junction in this skin biopsy taken from an area with a visible rash. With SLE such deposition can be found in skin uninvolved by a rash, whereas with DLE the immune complexes are found only in involved skin.

94 Vasculitis Vasculitis in arteries throughout the body can account for signs and symptoms from a variety of organ involvements. Seen here is an artery with extensive vasculitis with chronic inflammatory cells.

95 SLE is associated with a peculiar periarteriolar fibrosis in the spleen, as shown here.

96 Kidney biopsy WHO classification of lupus nephritis is based on light, immunofluorescence, and electron microscopic findings.

97 WHO classification of lupus nephritis
immunofluorence electron microscopy Pattern mesangial peripheral mesangial subendothelial subepithelial Ⅰnormal ⅡA mesangial deposit ⅡB mesangial hypercellularity Ⅲ focal segmental GN Ⅳ diffuse GN Ⅴ membranous GN

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99 Semiquantitative assessment of activity and chronicity
Active indicators cellular proliferation, necrosis, karyorrhexis, cellular crescents, wire loops, hyaline thrombi, leukocytic infiltration, interstitial infiltration. Chronicity indicators glomerular sclerosis, fibrous crescents, interstitial fibrosis, tubular atrophy Indicators are scored on a scale of 0 to 3,with necrosis, karyorrhexis, and cellular crescents weighted two times. The maximum of activity is 24, and the maximum of chronicity is 12.

100 Diagnosis

101 Criteria for diagnosing lupus
The diagnosis of lupus is a clinical one made by observing symptoms. Lab tests provide only a part of the picture. The American College of Rheumatology has designated 11 criteria for diagnosis. To receive the diagnosis of lupus, a person must have 4 or more of these criteria:

102 Criteria of the ARA for the classification of SLE
1. Malar rash: Fixed erythema over malar areas, sparing nasolabial folds 2. Discoid rash: Erythematous raised patches with keratotic scaling and follicular plugging 3. Photosensitivity: Skin rash after exposure to sunlight, history or physical exam 4. Oral ulcers: Oral or nasopharyngeal, painless, by physical exam 5. Arthritis:Tenderness, swelling, effusion in 2 or more peripheral joints 6. Serositis: A) pleuritis or B) pericarditis 7. Renal disorder A) proteinuria>0.5g/24hour or 3+ or B) cellular casts 8. Neurological disorder: A) seizures or B) psychiatric disorder (having excluded other causes, e.g. drigs) 9. Haematological disorder: A) haemolytic anaemia or B) leucopenia or C) thrombocytopenia 10. Immunologic disorder: A) positive LE cells or B) raised anti-native DNA antibdy binding or C) anti-Sm antibody or D) false positive serological test for syphilis. 11. Positive antinuclear antibody:

103 Management and treatment

104 1. Monitoring the lupus patients
It cannot be emphasized too strongly that lupus is a disease requiring regular and careful follow-up. Important initial advice should be given about avoiding UV light, infections, extreme stress or fatigue Laboratory test—blood test, ESR, C3,IC, liver function tests and anti-dsDNA.

105 2. Grading clinical activity
The highly variable nature of the syndrome Evaluation of lupus activity is the base or beginning of therapy. Non-life-threatening features such as arthralgia, skin rash, RP, alopecia Severe complication such as renal, cerebral and heart involvement.

106 SLE disease activity index (SLEDAI)
Clinical feature score seizure , psychosis , organ brain syndrome visual disturbance, cranial nerve disorder lupus headache, cerebrovascular accidents, vasculitis arthritis myositis urinary casts, hematuria, proteinure, pyuria rash, alopecia, mucosal ulcers, pleurisy, pericarditis low complement, increased DNA binding fever thrombocytopenia, leucopenia

107 3. Clinical therapy There are four main groups drugs useful in the treatment of lupus: the non-steroid anti-inflammatory drugs, anti-malarials, corticosteroid and cytotoxic drugs. How to treat lupus is a kind of art. Which and the dosage of drugs will be used to treat the patient depend on lupus activity.

108 Treatment principles Depends on disease severity
Fever, skin, musculoskeletal and serositis = milder disease CNS and renal involvement – aggressive Rx Emergencies: - severe CNS involvement systemic vasculitis profound thrombocytopenia (TTP-like syndrome) rapidly progressive nephritis diffuse alveolar hemorrhage

109 Medications used Steroids Cyclophosphamide Azathioprine Mycophenolate
Chloroquine (Rituximab) Plasma exchange/ IVIG NSAIDS

110 Disease-modifying antirheumatic drugs
Disease-modifying antirheumatic drugs (DMARDs) are used preventively to reduce the incidence of flares, the process of the disease, and lower the need for steroid use; when flares occur, they are treated with corticosteroids. DMARDs commonly in use are antimalarials and immunosuppressants (e.g. methotrexate and azathioprine). Hydroxychloroquine is an FDA-approved antimalarial used for constitutional, cutaneous, and articular manifestations, whereas cyclophosphamide is used for severe glomerulonephritis or other organ-damaging complications.

111 Steroids in Lupus Dermatitis (local) Polyarthritis Serositis
Steroid responsive Dermatitis (local) Polyarthritis Serositis Vasculitis Hematological Glomerulonephritis (most) Myelopathies Steroid non-responsive Thrombosis Chronic renal damage Hypertension Steroid-induced psychosis Infection

112 Preventive care Medication-related (steroid) complications (Ca, vit D, bisphosphonates) Aggressive BP and lipid control Immunization (complement deficient) Stress-dose steroid protocols for patients on maintenance corticosteroids (surgery/ infection) Avoid UV exposure Avoid estrogen therapies Avoid sulfa-containing medications Pregnancy planning

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114 Mildly active lupus Category I arthritis, arthralgia, myalgia, fatigue, mild mucocutaneous involvement, low-grade fever, mild serositis, lupus headache combination of NSAID and / or antimalarials(chloroquine, hydroxychloroquine) . The drug of choice is hydroxychloroquine (200 mg BD for 3 months and then 200 mg daily). Prednisolone remain the drugs of first choice to control lupus activity. Low dosage <=10mg/d can be used therapy (Prednisolone mg/kg/day)

115 Category II (Moderate SLE) high-grade fever, toxaemia, severe mucocutaneous manifestations, marked photosensitivity, moderate to severe serositis, lupus pneumonitis, mild to moderate myocarditis, mesangioproliferative or minimal change lupus nephritis, haemolytic anaemia and thrombocytopenia prednisolone 1 mg/kg orally per day High dose of steroid must be continued till disease activity is well controlled that usually takes up to 6 weeks when it should be tapered off slowly over 6 to12 months. In a toxic appearing patient, the administration of intravenous pulse methylprednisolone (15 mg/kg, max. 1 g) over an hour for 3 or 5 consecutive days may achieverapid control of lupus activity.

116 Category III (Severe SLE) organ/life-threatening features such as : focal/diffuse proliferative glomerulonephritis with or without azotaemia/hypertension lupus cerebritis with recurrent seizures, acute confusional state, coma; systemic necrotizing vasculitis such as one causing peripheral gangrene, GI bleeding or mononeuritis ultiplex A combination therapy consisting of high-dose daily oral prednisolone (40-60 mg/day) and intravenous cyclophosphamide pulses (0.75 gm/m2, maximum of 1 g, over 1 hour) is recommended. The cyclophosphamide pulses are given once a month for 6 months by which time usually remission is achieved and then a aintenance pulse is administered every 3 months for a total of 2 years of cytotoxic therapy. Prednisolone is tapered off or reduced to a very low dose i.e mg per day by 6 months.

117 resistant thrombocytopenia or haemolytic anaemia
Category IV (SLE with miscellaneous features) antiphospholipid syndrome (recurrent DVT, CVAs, recurrent foetal loss etc.), pure membranous lupus nephritis, chronic sclerosing lupus nephritis, seizures without other evidence of lupus activity, behavioural disorders without other serious manifestations, resistant thrombocytopenia or haemolytic anaemia resistant thrombocytopenia or haemolytic anaemia Immunosuppressive therapy does not play any significant role in these conditions. Treatment of antiphospholipid syndrome. Heparin and warfarin should be started simultaneously so as to allow an overlap of about 5 days. INR should be adjusted between 3 and 4 on long-term warfarin therapy. The duration of warfarin therapy is life-long in patients with recurrent venous thrombosis. For refractory thrombocytopenia, danazol may be useful.

118 regimen for induction of remission (the first 6 months), which is then maintained with azathioprine mg/kg/day for about 2 years.

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120 Biological agents Abatacept Blocks CD28-mediated costimulation
Abetimus Blocks the production of anti-dsDNA antibodies Anakinra (IL-1 receptor antagonist) Blocks IL-1 signalling Atacicept (TACI-Ig) Soluble TACI receptor that binds to BLyS and APRIL Reduction in B cells and immunoglobulin levels Infliximab (anti-TNF) Blocks TNF Rituximab (anti-CD20 mAb) Depletion of B cells Tocilizumab (anti-IL-6 receptor mAb) Blocks IL-6

121 Treatment of SLE Arthritis, arthralgias, myalgias: NSAIDS,
anti-malarials (eg. Plaquenil), Steroids-injections, oral methotrexate Photosensitivity, dermatitis avoid Sun exposure topical steroids Plaquenil Weight loss and fatigue steroids Abortion, fetal loss ASA immunosuppression Thrombosis anti-coagulants Glomerulonephritis steroids pulse cytotoxics mycophenylate mofetil CNS disease anti-coagulants for thrombosis Steroids and cytotoxics for vasculitis Infarction (secondary to vasculitis) cytotoxics prostacyclin Cytopenias

122 Management of proliferative (class III–IV) lupus nephritis
Management of proliferative (class III–IV) lupus nephritis.39 Systemic lupus erythematosus patients with proliferative nephritis may be stratified into those with moderate-to-severe versus severe disease based on impairment of renal function (increase in serum creatinine ≥30% and/or proteinuria ≥3.0 g/day) and/or presence of adverse renal biopsy histological findings (crescents and/or fibrinoid necrosis >25% of glomeruli, chronicity index >4 or chronicity index >3 and activity index >10). Management of proliferative (class III–IV) lupus nephritis.39 Systemic lupus erythematosus patients with proliferative nephritis may be stratified into those with moderate-to-severe versus severe disease based on impairment of renal function (increase in serum creatinine ≥30% and/or proteinuria ≥3.0 g/day) and/or presence of adverse renal biopsy histological findings (crescents and/or fibrinoid necrosis >25% of glomeruli, chronicity index >4 or chronicity index >3 and activity index >10). Induction therapies start with high-dose glucocorticoids (intravenous (IV) methylprednisolone 1 g/day ×3 days and/or prednisone 1 mg/kg per day by mouth, then slow taper). For cyclophosphamide (CY) therapy, the National Institute of Health regimen includes seven monthly pulses of intravenous cyclophosphamide (0.5–1.0 g/m2). Alternatively, the Euro-Lupus regimen (six fortnightly pulses intravenous cyclophosphamide 500 mg) may be used. During maintenance therapy, low-dose background glucocorticoids are given (prednisone 0.25 mg/kg by mouth every other day). ACE, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; AZA, azathioprine; K/DOQI, Kidney Disease Outcomes Quality Initiative; MMF, mycophenolate mofetil. Bertsias G K et al. Ann Rheum Dis 2010;69: ©2010 by BMJ Publishing Group Ltd and European League Against Rheumatism

123 Management of renal lupus based on our own current practice.
Ioannou Y , Isenberg D A Postgrad Med J 2002;78: Copyright © The Fellowship of Postgraduate Medicine. All rights reserved.

124 Other therapy Plasma exchange Intravenous Immunoglobulin
Stem cell transplantation Immune therapy ( anti-IL10, anti-CD20, and immune tolerance therapy)

125 SLE and pregnancy SLE has been stable for more than 1 year.
Prednisone is no more than 10mg/d, and cytotoxic drug has been stopped for more than 6 moth. SLE patients can plan to have a baby.

126 Case #1 30 yo female with polyarthritis, fever, malaise, and malar rash

127 Lab Work-up  CBC Direct Coomb’s Platelet Count Urinalysis
Anemia in 60-70% (usu. normo/normo; hemolytic in 10%);  WBC in 50% Thrombocytopenia in 15-30% UA: RBCs; +/-casts; proteinuria

128 Which of the following is the probable diagnosis:
A. Dermatomyositis B. Scleroderma C. Rheumatoid arthritis D. Polyarteritis nodosa E. SLE

129 Case #1 30 yo female with polyarthritis(1), fever, malaise, and malar rash(2)

130 Systemic Lupus Erythematosus Lab Work-up
CBC Direct Coomb’s Platelet Count Urinalysis Anemia (3) in 60-70% (usu. normo/normo; hemolytic in 10%);  WBC in 50% Thrombocytopenia (3) in 15-30% UA: RBCs; +/-casts; proteinuria(4)

131 Which of the following is the probable diagnosis:
A. Dermatomyositis B. Scleroderma C. Rheumatoid arthritis D. Polyarteritis nodosa E. SLE ANSWER: E

132 Case 2: History A 36-year-old female is seen for migratory arthritis of 6 months’ duration. She also reports some fatigue and a photosensitive skin rash. ROS notes: Patchy hair loss 4 months ago that regrew Aphthous-like mouth ulcers every 4 to 6 weeks A diagnosis of “walking pneumonia” made last month based on symptoms of pleuritic chest pain 23

133 Case 2: Objective Findings
Pain with mild synovitis over the MCPs and PIPs Rash over her face, legs, and trunk Hgb = 12.1; ESR = 33 UA = 3+ protein ANA = 1:640 titer 24

134 Case 2: Question With this clinical history, what is the most important thing to do now? A. Start an NSAID for the joint pain B. Start hydroxychloroquine to treat the rash and prevent recurrent pleurisy C. Fully evaluate her renal status and initiate appropriate therapy D. Start prednisone at 80 mg qd 25

135 Case 2: Answer C. Fully evaluate her renal status Don’t Wait
Aggressively evaluate renal status if the urinalysis is abnormal in SLE patients 26

136 Case 2: History UA = 3+ protein(5) ANA = 1:640 titer(6)
A 36-year-old female is seen for migratory arthritis (1) of 6 months’ duration. She also reports some fatigue and a photosensitive skin rash.(2) ROS notes: Patchy hair loss 4 months ago that regrew Aphthous-like mouth ulcers(3) every 4 to 6 weeks A diagnosis of “walking pneumonia” made last month based on symptoms of pleuritic (4)chest pain UA = 3+ protein(5) ANA = 1:640 titer(6) 23

137 Prognosis Benign to rapidly progressive
Better for isolated skin + musculoskeletal disease vs renal and CNS Death rate 3X age-comparable general population Mortality Nephritis (most within 5 yrs of symptoms) Infectious (active SLE + Rx – most common) CVS disease (50X more MI than other woman) Malignancy (chronic inflammation + Rx)

138 Summary Autoimmune disorder Multiple manifestations
Aggressive investigation and treatment Continued surveillance

139 AMERICAN COLLEGE OF RHEUMATOLOGY (ACR) CRITERIA FOR DIAGNOSIS OF SLE
Serositis (Pleurisy, pericarditis) Oral ulcers Arthritis Photosensitivity Blood disorders (Leukopenia, thrombocytopenia) Renal involvement Antinuclear antibodies (ANA) Immunologic phenomena [false-positive Rapid Plasma Reagin (RPR)] Neurologic disorder Malar rash Discoid rash

140 Course and prognosis An episodic course is characteristic, with exacerbations and complete remissions that may last for long periods. These remissions may occur even in patients with renal disease. A chronic course is occasionally seen. Earlier estimates of the mortality in SLE were exaggerated; 10-year survival rate is about 90%. In most cases the pattern of the disease becomes established in the first 10 years; if serious problems have not developed in this time, they are unlikely to do so. The arthritis is usually intermittent. Chronic progressive destruction of joints as seen in RA and OA occurs rarely, but a few patients develop deformities such as ulnar deviation.

141 Summary - Key symptoms Arthralgia Alopecia Discoid lesions Fever
Malar rash Oral ulcer Photosensitivity Weight loss

142 Summary - Key signs A patient must have 4 or more of the following 11 criteria to be classified as having SLE - Malar rash - Discoid rash - Photosensitivity - Oral ulcer - Arthritis - Serositis - Renal disease - Neurologic disease - Hematologic disorders - Immunologic abnormalities - Positive antinuclear antibodies (ANA)

143 Summary - Key tests ANA Anti-dsDNA Anti-Sm
Complement levels (especially C3) False-positive test for syphilis

144 Summary – Key treatment
Corticosteroids: Solu-Medrol, prednisone Immunosuppressive drugs: methotrexate (MTX), azathioprine Antimalariais: hydroxychloroquine NSAIDs

145 Thank you very much!


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