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Systemic Lupus Erythematosus PowerPoint Presentation

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Description : This presentation is suitable for undergraduate medical students and was used for teaching the subject to them. It is based on the Textbook of Pathology by Robins.

Tags : systemic lupus erythematosus,SLE,autoimmune disease,multiple organs,immune,diagnosis

Published on : May 07, 2022 | Views : 1777 | Downloads : 9

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Dr (Col) Mahendra N Mishra Systemic Lupus Erythematosus
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Definition SLE is an autoimmune disease involving multiple organs, characterized by a vast array of autoantibodies, particularly antinuclear antibodies (ANAs), in which injury is caused mainly by deposition of immune complexes and binding of antibodies to various cells and tissues Onset acute or insidious, is very heterogeneous, typically a chronic, remitting & relapsing, often febrile, illness Injury to the skin, joints, kidney, and serosal membranes is most prominent, but virtually any organ
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Epidemiology Prevalence ~1 in 2500 in certain populations childbearing women : 1 in 700 female-to-male ratio of 9: 1 in the reproductive age group of 17 - 55 yrs, only 2 :1 for disease developing during childhood or after 65 years Race – 2 x in blacks & Hispanics as compared to whites India: reported prevalence of SLE ranges from 14 - 60 per 105
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Antibodies How do you express antibody levels ? Diagnosis and Rx ANAs 1) DNA, (2) histones, (3) nonhistone proteins bound to RNA, and (4) nucleolar antigens
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Diagnosis if 4 of the clinical and immunologic criteria are present at any time (not necessarily concurrently), including at least one clinical and one immunologic criterion Methods : enzyme linked immunosorbent assays (ELISA) or indirect Immunofluorescence ELISA is non-speciﬁc and less useful as a diagnostic test whereas ANA IFA is a more accurate test and the gold standard Other antibodies
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4 Staining patterns of ANA. (A) Homogeneous or diffuse staining of nuclei is typical of antibodies reactive with dsDNA, nucleosomes, and histones, and is common in systemic lupus erythematosus. (B) Speckled pattern is seen with antibodies against various nuclear antigens, including Sm and RNPs. (C) The pattern of staining of anti-centromere antibodies is seen in some cases of systemic sclerosis, Sjögren syndrome, and other diseases. (D) Nucleolar pattern is typical of antibodies against nucleolar proteins and represents antibodies to RNA (SSE)
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such as red cells, platelets, and lymphocytes; Antiphospholipid antibodies (APA): react with proteins in complex with phospholipids (in 30 - 40%) of lupus patients actually specific for epitopes of plasma proteins that are revealed when the proteins are in complex with phospholipids; e.g. prothrombin, annexin V, β2-glycoprotein I, protein S, & protein C Antibodies against the phospholipid-β2-glycoprotein complex to cardiolipin antigen, used in syphilis serology (false +) Some of these antibodies interfere with APTT, Referred to as lupus anticoagulants Despite the observed clotting delays in vitro, however, patients with APA, have complications related to excessive clotting (a hypercoagulable state), such as thrombosis
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Pathogenesis Failure of the mechanisms that maintain self-tolerance; role of genetic & environmental factors; MHC and multiple non-MHC genes High risk in family members, 20% of clinically unaffected 1st degree relatives of SLE patients have autoab & other immune abnormalities >20% concordance in monozygotic twins as compared with dizygotic twins (1% - 3%) Specific alleles of the HLA-DQ locus have been linked to the production of anti–dsDNA, anti-Sm, and APA, although the relative risk is small A Protective Role for the HLA-DR6 Alleles DRB1*13:02 and *14:03
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Pathogenesis (2) inherited deficiencies of early complement components, such as C2, C4, or C1q. Lack of complement may impair removal of circulating immune complexes by the mononuclear phagocyte system, thus favoring tissue deposition GWAS show other genetic loci that may be associated with SLE Many of these loci encode proteins involved in lymphocyte signalling & IFN responses, both of which may play a role in lupus pathogenesis
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Immunologic Factors several immunologic aberrations that collectively may result in the persistence and uncontrolled activation of self-reactive lymphocytes self-tolerance failure in B cells (due to central / peripheral causes) Activation of CD4+ helper T cells specific for nucleosomal antigens that escape tolerance and help B cells to produce high-affinity pathogenic autoantibodies TLR engagement by nuclear DNA and RNA contained in immune complexes may activate B lymphocytes Type I IFN play a role in lymphocyte activation in SLE High levels type I IFN and a molecular signature in blood cells suggesting exposure to these cytokines has been reported in SLE patients and correlates with disease severity
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Environmental Factors Exposure to ultraviolet (UV) light exacerbates sex hormones and partly related to unknown genes on X chromosome SLE-like response in human Drugs such as hydralazine, procainamide, and D penicillamine can induce an lupus like state
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In this hypothetical model, susceptibility genes interfere with the maintenance of self-tolerance, and external triggers lead to persistence of nuclear antigens. The result is an antibody response against self nuclear antigens, which is amplified by the action of nucleic acids on dendritic cells (DCs) and B cells, and the production of type 1 interferons. IFN, Interferon; TLRs, Toll-like receptors.
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Mechanisms of Tissue Injury immune complexes (type III hypersensitivity) DNA–anti-DNA complexes can be detected in the glomeruli and small blood vessels in animal models Low levels of serum complement (20 to consumption of complement proteins) and granular deposits of complement and Ig in glomeruli LE bodies: ANAs bind to exposed cell nuclei with loss of chromatin pattern (In tissues); In blood LE cell Cytopenias : Autoantibodies specific for RBCs, leukocytes & platelets opsonize them promoting their phagocytosis & destruction ITP -10% antibodies against Platelet glycoproteins
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Mechanisms of Tissue Injury 10 versus 20 Antiphospholipid antibody syndrome venous and arterial thromboses may be associated with recurrent spontaneous miscarriages and focal cerebral / ocular ischemia Mechanism ?? Ab against, clotting factors, and endothelial cells Neuropsychiatric manifestations attributed to antibodies that cross the blood-brain barrier and react with neurons or receptors for various neurotransmitters
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Morphology Blood Vessels An acute necrotizing vasculitis involving capillaries, small arteries, and arterioles may be present in any tissue; arteritis---- fibrinoid necrosis (acute stage) In chronic stages, vessels undergo fibrous thickening with luminal narrowing Kidneys Up to 50% of SLE patients have clinically significant renal involvement mainly in the form of glomerulonephritis (GN) and tubulointerstitial nephritis; GN due to deposition of immune complexes on the glomerular basement membrane, in the mesangium, and sometimes throughout the glomerulus
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Patterns of renal involvement Minimal mesangial lupus nephritis (class I) very uncommon, changes only with EM /IM (immune complex deposits) Mesangial proliferative lupus nephritis (class II) mesangial cell proliferation, often accompanied by accumulation of mesangial matrix, and granular mesangial deposits of Ig and complement without involvement of glomerular capillaries Focal lupus nephritis (class III) defined by involvement of < 50% of glomeruli; lesions may be segmental or global ------- swelling and proliferation of endothelial and mesangial cells, leukocyte accumulation, capillary necrosis, and hyaline thrombi : extra capillary proliferation associated with focal necrosis and crescent formation
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Diffuse lupus nephritis (class IV) most common and severe form of lupus nephritis > 50% of glomeruli segmental (IV-S) or global(IV-G) involvement- show proliferation of endothelial, mesangial, and epithelial cells latter producing cellular crescents that fill Bowman’s space; . Subendothelial immune complex deposits may cause circumferential thickening of the capillary wall, forming “wire loop” structures on light microscopy Membranous lupus nephritis (class V) is characterized by diffuse thickening of the capillary walls due to deposition of subepithelial immune complexes, similar to idiopathic membranous nephropathy The immune complexes are usually accompanied by increased production of basement membrane– like material This lesion typically causes severe proteinuria or nephrotic syndrome and may occur concurrently with focal or diffuse lupus nephritis
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Lupus nephritis. (A) Focal proliferative glomerulo- nephritis, with two focal necrotizing lesions at the 11 o’clock and 2 o’clock positions (H&E stain). Extra capillary proliferation is not prominent in this case. (B) Diffuse proliferative GN. Note the marked increase in cellularity throughout the glomerulus (H&E stain). (C) Lupus nephritis showing a glomerulus with several “wire loop” lesions representing extensive sub-endothelial deposits of immune complexes (PAS) EM of a renal glomerular capillary loop from a patient with lupus nephritis. Subendothelial dense deposits (arrowheads) correspond to “wire loops” seen by light microscopy. B (with arrow) refers to the basement membrane. (E) Deposition of IgG antibody in a granular pattern, detected by IF
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Renal lesions Advanced sclerosing lupus nephritis (class VI) is characterized by sclerosis of more than 90% of the glomeruli and represents end-stage renal disease Rarely tubulointerstitial lesions may be the dominant abnormality Immune complexes similar to those in glomeruli are present in the tubular or peritubular capillary basement membranes Occasionally, there are well-organized B-cell follicles in the interstitium, with plasma cells that may be sources of autoantibodies
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Skin, Joints , Skin characteristic erythema affects the face along the bridge of the nose and cheeks (the “butterfly” rash) in approximately 50% of patients, and a similar rash may be seen on the extremities and trunk ME dermis : variable edema and perivascular inflammation Vasculitis with fibrinoid necrosis may be prominent; sunlight incites or accentuates the erythema Joints a nonerosive synovitis with little deformity, which contrasts with RA CNS No clear morphologic abnormalities account for the neuropsychiatric symptoms of SLE; Noninflammatory occlusion of small vessels by intimal proliferation is sometimes noted, which may be due to endothelial damage by autoantibodies or immune complexes
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H&E-stained section shows liquefactive degeneration of the basal layer of the epidermis and edema at the dermoepidermal junction (DE jn) ; IF deposits of Ig at DE jn mitral valve in SLE . The vegetations attached to the margin of the thickened valve leaflet are indicated by arrow
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Pericarditis and Other Serosal Cavity Inflammation of the serosal lining membranes may be acute, subacute, or chronic acute phases, the mesothelial surfaces are sometimes covered with fibrinous exudate Later they become thickened, opaque, and coated with a shaggy fibrous tissue that may lead to partial or total obliteration of the serosal cavity. Pleural and pericardial effusions may be present
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CVS Any or all of the 3 layers may be involved Symptomatic or asymptomatic pericardial involvement is present in up to 50% of patients Myocarditis, or mononuclear cell infiltration, is less common and may cause resting tachycardia and ECG abnormalities Valvular abnormalities, primarily of the mitral and aortic valves, manifest as diffuse leaflet thickening that may be associated with dysfunction (stenosis and/or regurgitation) Valvular endocarditis (called LibmanSacks endocarditis) was more common before the widespread use of steroids – nonbacterial verrucous endo-carditis takes the form of single or multiple 1- 3-mm warty deposits on any heart valve, distinctively on either surface of the leaflets; much bigger in IE
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Other organs Spleen Splenomegaly, capsular thickening, and follicular hyperplasia are common Lungs In addition to pleuritis and pleural effusions, which are present in almost 50% of patients, in some cases, there is chronic interstitial fibrosis and secondary pulmonary hypertension None of these changes is specific for SLE
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Clinical features Presentation - highly variable; acute or insidious in its onset diagnosis relies on a constellation of clinical, serologic & morphologic changes course of the disease is variable and unpredictable: may as PUO the patient is a young woman with some, but not necessarily all, of the following features: a butterfly rash over the face, fever, pain but no deformity in one or more peripheral joints (feet, ankles, knees, hips, fingers, wrists, elbows, shoulders), pleuritic chest pain, and photosensitivity.
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renal involvement, including hematuria, red cell casts, proteinuria, and in some cases the classic nephrotic syndrome hematologic derangement is seen in virtually every case, but in some patients anemia or thrombocytopenia may be the presenting manifestation as well as the dominant clinical problem mental aberrations, including psychosis or convulsions, or coronary artery disease may be prominent clinical problems SLE are also prone to infections, presumably because of underlying immune dysfunction and treatment with immunosuppressive drug
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Chronic Discoid Lupus Erythematosus skin manifestations may mimic SLE, but systemic manifestations are rare ; ~35% of patients test positive for generic ANAs, but antibodies to double-stranded DNA are rarely present, IF deposits of C3 and Ig in BM: ~5- 10% of patients develop multisystem manifestations Subacute Cutaneous Lupus Erythematosus features intermediate between SLE and DLE skin rash tends to be widespread, superficial, and nonscarring (though exceptions occur). Secondly, most patients have mild systemic symptoms consistent with SLE
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