BL.2.12: SLE and Vasculitis, Polymyositis Flashcards
Describe the clinical, laboratory, and X-ray features of systemic lupus erythematosis (SLE), including the organs involved and serologies.
Criteria for disease classification include 1. Malar rash, 2. Discoid rash, 3. Photosensitivity, 4. Oral ulcers, 5. Arthritis, 6. Serositis, 7. Renal involvement, 8. Central nervous system involvement (seizures of psychosis), 9. Hematologic disorders (hemolytic anemia, leucopenia, lymphopenia, thrombocytopenia), 10. Immunologic disorders (antibodies to native DNA, Smith antigen, anticardiolipin IgG or IgM, lupus anticoagulant, or a false-positive serologic test for syphilis), and 11. Antinuclear antibody (ANA). Positivity for at least 4 of the 11 criteria allows classification of a patient having SLE.SLE is a chronic, systemic autoimmune disease which affects multiple organ systems including the skin, joints, serosal surfaces (pleura and pericardium), kidneys, central nervous system, lungs, and hematologic system. For most of the disease manifestations of SLE, antibody-mediated effector mechanisms appear to be operative. Organ damage can result from either type II mediated immunologic damage (direct antibody binding to specific cells or tissues), or type III mediated immunologic damage (formation of immune complexes).Over 95% of patients with SLE have evidence of excessive ANA production, as evidenced by elevated serum levels. They can also have antibodies to RBC’s, nerves, and phospholipids. Xray?
Explain the difference between organ specific autoimmunity and systemic autoimmunity.
Organ specific autoimmunity is defined as an immune response directed against a single autoantigen or a restricted group of autoantigens within a given organ. The result is autoimmune destruction of only those organs expressing the relevant autoantigens. Ex. myasthenia gravis, Goodpasture’s syndrome, thyroiditis, type 1 diabetesSystemic autoimmunity is defined as an immune response against multiple autoantigens rather than to autoantigens of a given organ. The resulting disease affects multiple organs both on the basis of circulating immune complexes and direct immune attack against organs. Ex. SLE, Sjogren’s Syndrome
Discuss the epidemiology and genetics of SLE including the predisposing factors and environmental factors that can modulate disease.
Although the etiology of SLE is unclear, there is overwhelming evidence for a genetic predisposition. Association of SLE with HLA-DR3; and C4A null alleles (strongest association).Other genes associated with innate immunity and interferon alpha pathways may predispose to developing SLE.The expression of disease manifestations can be greatly affected by environmental factors. Sex hormones: There is a markedly increased incidence of SLE in women of childbearing age.Sun exposure: SLE skin disease can be exacerbated by exposure to U.V. light (photosensitivity). Indeed, patients can sometimes have marked systemic or generalized flares of disease after excessive sun exposure.
Explain the pathophysiology of SLE.
For most of the disease manifestations of SLE, antibody-mediated effector mechanisms appear to be important.Organ damage can result from either type II mediated immunologic damage (direct antibody binding to specific cells or tissues), or type III mediated immunologic damage (formation of immune complexes).Specific antibody disease causes hemolytic anemia, antiphospholipid antibodies, Neuropsychiatric manifestations (depression, cognitive dysfunction, psychosis, organic brain syndromes, and seizures). Autoantibodies that bind to neurons (anti-neuronal antibodies) may account for some of these CNS manifestations.Immune complex mediated diseases: The most important determinant of prognosis in SLE is the presence and degree of kidney involvement- Lupus nephritis. They also have antibodies to dsDNA which forms immune complexes that get stuck in the kidney.
Discuss the treatment of SLE as it relates to the pathophysiology.
Treatment of SLE is directed at decreasing exposure to disease triggers (sun blocks), decreasing the inflammatory response [NSAIDs, and corticosteroids (both topical and systemic)], and decreasing the cellular/humoral immune responses (anti-malarials; immunosuppressive drugs including azathioprine, mycophelolate, and cyclophosphamide; and rituximab).
Name the different types of vasculitis according to the Chapel hill Consensus Conference classification.
Large vessel: giant cell arteritis, Takayasu’s arteritisMedium vessel: Polyarteritis nodosa, Kawasaki’s diseaseSmall vessel: Antineutrophil cytoplasmic antibody + (Wegener’s syndrome, Churg-Strauss Syndrome, Microscopic Polyangiitis)ANCA (-): HSP, Essential cryoglobulinemic vasculitis, cutaneous leukocytoclassic angiitis
Describe the clinical features and the laboratory abnormalities suggestive of vasculitis.
Signs/Symptoms: Common clinical features, including skin lesions, constitutional symptoms (fever, anorexia, weight loss, weakness, fatigue) and musculoskeletal symptoms (arthralgias, arthritis, myalgias, peripheral neuropathy), are found to some extent in all systemic vasculitides as noted above.Laboratory features: reflect systemic inflammation – anemia of inflammatory disease, thrombocytosis, low albumin, elevated sedimentation rate and C-reactive protein, polyclonal gammopathy; possibly elevated liver enzyme tests, low complement levels, cryoglobulins
Discuss the different immunopathogenic mechanisms that mediate vasculitis.
Immune complexes (IC): Animal models of serum sickness, human serum sickness induced by horse immunoglobulins (anti-venoms), and the demonstration of hepatitis B surface antigen and IgM in an arterial wall of a patient with polyarteritis nodosa suggest that IC can mediate inflammatory vessel disease. This is followed by deposition of circulating IC at the vascular endothelium, the activation of complement, and the attraction of PMNs.In vitro, antiendothelial antibodies can damage endothelial cells by both antibody-dependent cellular cytotoxicity (ADCC) and complement activation mechanisms.T-cell responses in the initiation and perpetuation of vascular injury have been suggested in Takayasu’s, Wegener’s, and giant cell arteritis.A wide variety of infectious agents can infect endothelial cells. Infected endothelial cells promote binding of IC and PMNs to the endothelium, express MHC class II genes, enhance local lymphocyte proliferation, and release stimulatory and proliferative cytokines. These changes may promote the vascular inflammatory response and initiate a T cell proliferative response.
Distinguish the different types of ANCAs and discuss their role in the pathogensis of vasculitis.
The cytoplasmic staining or c-ANCA (Wegener’s granulomatosis) binds to proteinase 3 (PR3) found in the primary granules of the PMN. The perinuclear staining or p-ANCA (microscopic polyangiitis) binds to myeloperoxidase (MPO), another primary granule constituent which migrates to the perinuclear area with alcohol fixation of PMNs.ANCA are antibodies to antigens found in the cytoplasm of neutrophils. The binding of ANCA to the neutrophil cell surface leads to further neutrophil activation and possibly enhanced binding to vascular endothelial cells with resultant vascular damage. Although ANCA may not be essential for the initiation of the vasculitis, they may play a role in amplifying the inflammatory vascular response.
Discuss the treatment of vasculitis as it relates to the extent of organ involvement.
Treat or remove the inciting agent or antigen: drugs, infections – endocarditis, hepatitis B and CIn general, the pathogenic process, the extent of inflammation and vascular involvement, and the rate of progression of the disease determine the management of vasculitis. Glucocorticoids generally control the inflammatory features of vasculitis. Rapidly progressive disease with significant major organ involvement (lung, kidney, and gut) may require high-dose glucocorticoids and a cytotoxic drug such as cyclophosphamide. Plasmapheresis may be beneficial in hepatitis C-induced cryoglobulinemia and ANCA- positive vasculitides. Rituximab, an anti-CD20 B cell monoclonal antibody, has recently been shown to be efficacious as a treatment for severe ANCA-associated vasculitis.
In SLE, what are some of the theories for autoimmunity?
Autoreactive T cells (loss of T cell tolerance)Polyclonal B cell activation (increased production of all Ab, including self Ab)Molecular mimicry (An exogenous antigen with molecular similarities to autoantigens may be introduced to the immune system, resulting in an appropriate immune response which then cross-reacts with self-antigens.)Illicit help” - A foreign antigen may be combined with an autoantigen such that the foreign antigen may be processed and presented to the T cell
Describe the clinical and laboratory features of polymyositis and dermatomyositis including EMG and MRI findings.
Muscle weakness and low endurance are typically the main complaints in patients with PM/DM. Proximal extremity muscles are affected earliest and most severely leading to early complaints of difficulty with standing, rising from chairs, climbing stairs, and with brushing/washing their hair. Only half experience any muscle pain or tenderness.Skin disease including Gottron’s papules, heliotrope rash, V sign and shawl sign rash, mechanic’s hands, calcinosis cutis, periungual erythemaExtra muscular disease including: weight loss, fever, fatigue, trouble with other systems: GI, pulmonary, cardiac, musculoskeletal, vascular, antisynthetase syndromeEMG findings: a myopathic pattern - increased insertional activity (abnormally increased activity when the EMG needle is inserted) and spontaneous fibrillations, decreased amplitude of motor unit action potentials, and complex repetitive discharges.MRI findings: can demonstrate areas of muscle inflammation, edema with active myositis, fibrosis, and calcinosisLab findings: CPK elevated in the vast majority of patients with active disease. Other indicators of muscle injury may be elevated: aldolase, myoglobinemia, LDH, AST, ALT.
Discuss the clinical and laboratory features of the Anti-synthetase Syndrome including anti-synthetase antibodies.
Anti-synthetase Syndrome: Constellation associated with antisynthetase antibodies (e.g. anti- Jo-1 antibody): PM or DM presenting with fever (20%), arthritis (50%), mechanic’s hands (30%), Raynaud’s phenomenon (40%), and interstitial lung disease (ILD, 60%).
Contrast the cellular differences in the pathology of polymyositis and dermatomyositis.
Polymyositis: Endomysial distribution with mononuclear inflammatory cells surrounding and invading non-necrotic muscle fibers throughout the fascicle. The inflammatory cell infiltrates are primarily CD8+ T cells and macrophages with rare CD4+ T cells and dendritic cells.PM appears to be a direct CD8+ T cell-mediated muscle injury.Dermatomyositis: The inflammatory infiltrate (CD4+ T cells, B cells, macrophages, and dendritic cells) is concentrated in the perivascular, septal regions, and around the periphery rather than throughout the fascicle.Dermatomyositis is considered in part to be a complement-mediated vasculopathy.
List the evidence suggesting viral infections as a cause or triggering factor in polymyositis or dermatomyositis.
Viruses might initially trigger the disease process before being eliminated by the host’s immune response.Certain viral infections have been described to cause a form of inflammatory myositis (influenza, coxsackievirus, echoviruses).Viral particles (detected by electron microscopy) and RNA sequences (detected by virus- specific gene probes) have been detected in the muscle tissue of patients with DM and PM.HIV infection can be associated with PMHigher prevalence of antibodies to coxsackie B virus in juvenile DM compared to controls.Isolation of enterovirus from a few patients with PM/DM.Seasonal (spring) pattern of onset in patients with anti-Jo-1 antibodies.Microarray mRNA profiling in DM: predominance of interferon-responsive pathways suggesting an antiviral response.
