2INTRODUCTIONSystemic 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%.
41. Genetic factorMany studies have described familial aggregation of SLE % of lupus have at least one first or second degree relative with lupusIt 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.
5What 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.
62. 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.
7Allergy. 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.
83. 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.
9The 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.
104. Abnormal immune system Sustained presence of autoantigens: increased apoptosis , impaired clearance of apoptosisHyperactivity 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-10Defective regulatory mechanism.
11Autoimmine DiseasesAutoimmune diseases result from a break down of self tolerance
12Autoantibodies 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.
13Overview of the pathogenesis of SLE InfectionUV lightSelf AgExternal AgSkin cellAPCGenetic susceptibilityT cellT cellICAPCB cellTargetAbDefective IC clearance
14SLE 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.
22General symptomsThe 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.
23Fatigue 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.
24Raynaud’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)
25Dermatological involvement Up to 85% of SLEButterfly rashMaculopapular eruptionDiscoid lupusRelapsing nodular non-suppurative panniculitisVasculitic skin lesinLivedo reticularisPurpuric lesionsAlopeciaOral ulcer
5353 yo BF with severe generalized weakness, weight loss, and chronic psychosisAlopeciaPsychosisMalar rashArthritis
54Musculoskeletal 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
56Avacular necrosis of bone. It may be caused by prednisone therapy
57Kidney systemHaematuriaProteinure (>0.5g protein/d or 3+ )Cast
58Nervous systemThe 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.
59Hematological abnormalities Red blood cellsa 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.
60Platelets.thrombocytopenia (<100*109/L) appears to be mediated by anti-platelet antibodies or/and anti-phospholipid antibodies.
61White blood cellleucopenia (<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.
62Pulmonary manifestations Pleurisyit 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.
63Lung1) acute lupus pneumonitis: fever, dyspnea, cough with scanty sputum, hemoptysis, tachypnea and pleuritic chest pain.2) pulmonary hemorrhage3) 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.
66Cardiovascular 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 diseaseHypertension, cardiac failure
68SLE 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.
69Gastrointestinal and hepatic manifestation Esophagitis, dysphagia, nausea, vomiting: (drug related in most cases)Chronic intestinal pseudo-obstruction, mesenteric vasculitis, protein-losing enteropathyPancreatitisLupus hepatitis
70EyesThe 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
71Secondary sjogren’s syndrome Dry eyesDry mouthexocrine glands were infiltrated with lymphocytes
72Secondary 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.
75Deep 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.
79Autoantibodies 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 antigensanti-SSA, anti-SSBCell-specific autoantibodieslymphocytotoxic antibodies, anti-neurone antibodies, anti-erythrocyte antibodies, anti-platelet antibodiesAntibodies to serum componentsantiphospholipid antibodyanticoagulants antiglobulin (rheumatoid factor)
80Anti-nuclear antibodies The lupus erythematosus (LE) cellit has been superseded by the ANA and anti-dsDNA techniques.ANA is a screening testanti-Sm, anti-dsDNA antibodies are lupus specific antoantibodies.
81This 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.
82This rim (peripheral ) pattern of linear bright green staining around the peripheral of nuclei seen by immunofluorescence microscopy with a Hep2 cell substrate .dsDNA
85These 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.
86Immu-blotting method to detect anti-Sm, RNP, SSA, SSB, Jo1, Scl70 and ribosomal P.
87Antibodies 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
88Antinuclear Antibody (ANA) Most useful in SLESensitive but not specific for SLEAlso seen in drug-induced lupus, RA, scleroderma, chronic hepatitisSince non-specific for SLE other more specific antibodies were sought
89ANA: peripheral pattern If ANA titer is > 1:160, and there is a peripheral pattern, it strongly suggests SLE
90Anti-nDNA Antibody specific More specific than ANA Antibodies to “native” double-stranded DNA, a specific nuclear constituent that functions as an autoantigenOccurs in ~70% of patients with SLEIs for SLEspecific
91Anti-nDNA AntibodyUsed to confirm SLE in someone suspected of having SLE who has a positive ANAVirtually all patients with a positive Anti-nDNA antibody have a positive ANATherefore, don’t order if patient has a negative ANA
92Anti-Sm Antibody Specific for SLE Antibody to Smith (Sm) antigen Present in only 30% of patients with SLE (therefore not sensitive for SLE)
93Lupus band testImmunofluorescence 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.
94VasculitisVasculitis 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.
95SLE is associated with a peculiar periarteriolar fibrosis in the spleen, as shown here.
96Kidney biopsyWHO classification of lupus nephritis is based on light, immunofluorescence, and electron microscopic findings.
97WHO classification of lupus nephritis immunofluorence electron microscopyPattern mesangial peripheral mesangial subendothelial subepithelialⅠnormalⅡA mesangial depositⅡB mesangial hypercellularityⅢ focal segmental GNⅣ diffuse GNⅤ membranous GN
99Semiquantitative assessment of activity and chronicity Active indicatorscellular proliferation, necrosis, karyorrhexis, cellular crescents, wire loops, hyaline thrombi, leukocytic infiltration, interstitial infiltration.Chronicity indicatorsglomerular sclerosis, fibrous crescents, interstitial fibrosis, tubular atrophyIndicators 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.
101Criteria 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:
102Criteria of the ARA for the classification of SLE 1. Malar rash: Fixed erythema over malar areas, sparing nasolabial folds2. Discoid rash: Erythematous raised patches with keratotic scaling and follicular plugging3. Photosensitivity: Skin rash after exposure to sunlight, history or physical exam4. Oral ulcers: Oral or nasopharyngeal, painless, by physical exam5. Arthritis:Tenderness, swelling, effusion in 2 or more peripheral joints6. Serositis: A) pleuritis or B) pericarditis7. Renal disorder A) proteinuria>0.5g/24hour or 3+ or B) cellular casts8. 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) thrombocytopenia10. 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:
1041. 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 fatigueLaboratory test—blood test, ESR, C3,IC, liver function tests and anti-dsDNA.
1052. Grading clinical activity The highly variable nature of the syndromeEvaluation of lupus activity is the base or beginning of therapy.Non-life-threatening features such as arthralgia, skin rash, RP, alopeciaSevere complication such as renal, cerebral and heart involvement.
1073. Clinical therapyThere 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.
108Treatment principles Depends on disease severity Fever, skin, musculoskeletal and serositis = milder diseaseCNS and renal involvement – aggressive RxEmergencies: - severe CNS involvement systemic vasculitis profound thrombocytopenia (TTP-like syndrome) rapidly progressive nephritis diffuse alveolar hemorrhage
109Medications used Steroids Cyclophosphamide Azathioprine Mycophenolate Chloroquine(Rituximab)Plasma exchange/ IVIGNSAIDS
110Disease-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.
114Mildly active lupus Category I arthritis, arthralgia, myalgia, fatigue, mild mucocutaneous involvement, low-grade fever, mild serositis, lupus headachecombination 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)
115Category 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 thrombocytopeniaprednisolone 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.
116Category 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 ultiplexA 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.
117resistant 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 anaemiaresistant thrombocytopenia or haemolytic anaemiaImmunosuppressive 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 adjustedbetween 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.
118regimen forinduction of remission (the first 6 months), which is then maintained with azathioprine mg/kg/day for about 2 years.
120Biological agents Abatacept Blocks CD28-mediated costimulation AbetimusBlocks the production of anti-dsDNA antibodiesAnakinra (IL-1 receptor antagonist)Blocks IL-1 signallingAtacicept (TACI-Ig)Soluble TACI receptor that binds to BLyS and APRIL Reduction in B cells and immunoglobulin levelsInfliximab (anti-TNF)Blocks TNFRituximab (anti-CD20 mAb)Depletion of B cellsTocilizumab (anti-IL-6 receptor mAb)Blocks IL-6
121Treatment of SLE Arthritis, arthralgias, myalgias: NSAIDS, anti-malarials (eg. Plaquenil),Steroids-injections,oral methotrexatePhotosensitivity, dermatitisavoid Sun exposuretopical steroidsPlaquenilWeight loss and fatigue steroidsAbortion, fetal lossASAimmunosuppressionThrombosisanti-coagulantsGlomerulonephritissteroidspulse cytotoxicsmycophenylate mofetilCNS diseaseanti-coagulants for thrombosisSteroidsand cytotoxics for vasculitisInfarction (secondary to vasculitis)cytotoxicsprostacyclinCytopenias
125SLE 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.
126Case #130 yo female with polyarthritis, fever, malaise, and malar rash
127Lab 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
128Which of the following is the probable diagnosis: A. DermatomyositisB. SclerodermaC. Rheumatoid arthritisD. Polyarteritis nodosaE. SLE
129Case #130 yo female with polyarthritis(1), fever, malaise, and malar rash(2)
130Systemic Lupus Erythematosus Lab Work-up CBCDirect Coomb’sPlatelet CountUrinalysisAnemia (3) in 60-70% (usu. normo/normo; hemolytic in 10%); WBC in 50%Thrombocytopenia(3) in 15-30%UA: RBCs; +/-casts; proteinuria(4)
131Which of the following is the probable diagnosis: A. DermatomyositisB. SclerodermaC. Rheumatoid arthritisD. Polyarteritis nodosaE. SLEANSWER: E
132Case 2: HistoryA 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 regrewAphthous-like mouth ulcers every 4 to 6 weeksA diagnosis of “walking pneumonia” made last month based on symptoms of pleuritic chest pain23
133Case 2: Objective Findings Pain with mild synovitis over the MCPs and PIPsRash over her face, legs, and trunkHgb = 12.1; ESR = 33UA = 3+ proteinANA = 1:640 titer24
134Case 2: QuestionWith this clinical history, what is the most important thing to do now?A. Start an NSAID for the joint painB. Start hydroxychloroquine to treat the rash and prevent recurrent pleurisyC. Fully evaluate her renal status and initiate appropriate therapyD. Start prednisone at 80 mg qd25
135Case 2: Answer C. Fully evaluate her renal status Don’t Wait Aggressively evaluate renal status if the urinalysis is abnormal in SLE patients26
136Case 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 regrewAphthous-like mouth ulcers(3) every 4 to 6 weeksA diagnosis of “walking pneumonia” made last month based on symptoms of pleuritic (4)chest painUA = 3+ protein(5)ANA = 1:640 titer(6)23
137Prognosis Benign to rapidly progressive Better for isolated skin + musculoskeletal disease vs renal and CNSDeath rate 3X age-comparable general population MortalityNephritis (most within 5 yrs of symptoms)Infectious (active SLE + Rx – most common)CVS disease (50X more MI than other woman)Malignancy (chronic inflammation + Rx)
138Summary Autoimmune disorder Multiple manifestations Aggressive investigation and treatmentContinued surveillance
139AMERICAN COLLEGE OF RHEUMATOLOGY (ACR) CRITERIA FOR DIAGNOSIS OF SLE Serositis (Pleurisy, pericarditis)Oral ulcersArthritisPhotosensitivityBlood disorders (Leukopenia, thrombocytopenia)Renal involvementAntinuclear antibodies (ANA)Immunologic phenomena [false-positive Rapid Plasma Reagin (RPR)]Neurologic disorderMalar rashDiscoid rash
140Course and prognosisAn 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.
142Summary - Key signsA 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)
143Summary - Key tests ANA Anti-dsDNA Anti-Sm Complement levels (especially C3)False-positive test for syphilis