lupus, APS Flashcards
epidemiology, genetics, natural history, clinical expression including clinical subtypes, pathology, and disease pathogenesis. Antiphospholipid antibody syndrome.
What systems may require treatment for Lupus disease activity?
During the course of SLE, the following systems may require additional treatment; constitutional, mucocutaneous, CNS, musculoskeletal, cardiovascular, pulmonary, gastrointestinal, renal, ophthalmic, and hematologic.
What treatment adjustments in lupus define the severity of a disease flare by the BILAG system?
Severe, major or minor flares are defined as: Severe- an increase in prednisone dosage of 20 mg or greater, adding or increasing immunosuppression. Major- adding prednisone less than 20 mg, or an antimalarial, NSAID or topical steroid. Minor- Increasing symptomatic treatment such as topical steroids or NSAID. Otherwise, system should be scored as inactive, or never active.
What are the 2012 SLICC (Systemic lupus international collaborating clinics) criteria for diagnosis of SLE?
The diagnosis of systemic lupus requires presence of at least 4 of the following 17 features including 1/11 clinical and 1/6 immunologic or biopsy proven lupus nephritis. These criteria can be filled at any time, and have sensitivity and specificity of 95%.
What medications are known to work in systemic lupus erythematosus?
Effective treatment for SLE includes NSAID’s, glucocorticoids po, glucocorticoids I.V., glucocorticoids intraarticular, hydroxychloroquine (Plaquenil), methotrexate (Trexall), azathioprine (Imuran), cyclophosphamide (Cytoxan), mycophenolate mofetil (CellCept), mycophenolate sodium (Myfortic), rituximab (Rituxan), cyclosporine (Gengaf, Neoral), tacrolimus (Prograf), sirolimus (Rapamune) and belimubab (Benlysta), Canakinumab (Ilaris anti IL-1) and N-acetyl cysteine. abatacept (Orencia) improves proteinuria and depressed complement but does not reverse nephritis. Belimulab (Benlysta) was FDA approved for treatment of systemic lupus erythematosus in 3/2011.
What ethnic groups are predisposed to systemic lupus?
There is a much higher incidence of lupus compared with North Americans of European extraction in American blacks, Hispanics, Asian, and Caribbean blacks. African blacks are infrequently afflicted. Urban areas have higher incidence rates than rural. Female to male ratio is highest during childbearing ages (up to 15:1) than in childhood (3:1) in postmenopausal (8:1).
What manifestations of lupus are expressed differently in older patients?
SLE in older patients has a higher incidence of sicca syndrome, serositis, pulmonary involvement, and musculoskeletal involvement.
How often does lupus occur in family members of patients with lupus?
The concordance rate of SLE in monozygotic twins is 14 – 47%. 5 – 12% of relatives of SLE have SLE or increased frequency of anticardiolipin antibodies, ANA, C3 and C4 depression.
Why do patients with systemic lupus require higher than expected doses of glucocorticoids?
Activity of TLR7 and TLR9 receptors due to RNA and DNA stimulation decrease responsiveness to glucocorticoids.
What is the indication to treat thrombocytopenia in SLE?
Treatment for thrombocytopenia in SLE is indicated if symptomatic with less than 50,000 platelets, and for all patients with less than 20,000 platelets.
What genes occur in systemic lupus erythematosus with a hazard ratio > 5?
Loss of function complement mutations-C1q, C4A and B, C2, and mutated TREX1 (3’ Repair EXonuclease) that degrades DNA produce the highest hazard ratios. TREX1 is a DNA exonuclease and is also a component of the SET complex (group of 3 DNAases) that degrades nicked DNA during granzyme A-mediated cell death. Mutations result in chilblain lupus, and retinal vasculitis with cerebral dystrophy, and Cree encephalitis (genetic condition in Quebec Cree natives).
How many genes associated with SLE by GWAS studies?
GWAS studies identify 45 relevant gene loci by pathway-immunity, inflammation, cell adherence, repair, and tissue response to injury. These account for only 18% of overall susceptibility to SLE.
What are the criteria for an abnormal antiphospholipid antibody test?
Antiphospholipid antibody syndrome (APS) is due to antibodies to phospholipid. Useful tests include:- IgG and/or IgM antibodies to cardiolipin >40 units or >99 percentile, -antibodies to beta-2 glycoprotein 1 (apoprotein H) >99th percentile, or -abnormalities in clotting tests such as dAPTT(dilute), dRVVT, hex phase phospholipid clotting time. A false positive test for syphilis is too nonspecific for diagnostic purposes. Abnormalities must be documented on two or more occasions at least 12 weeks apart, and no more than five years prior to development of clinical manifestations. % with thromboembolism increases with degree and number of abnormal tests with OR ~5 with overlapping SD. Repeat testing at 12 wks for IgG and IgM aCL is positive in 20 and 15 %.
What clotting abnormalities increase the effect of antiphospholipid antibodies?
The risk of thrombosis in people with antiphospholipid antibody syndrome also depends upon other thrombophilic conditions. These include Factor V Leiden mutation, prothrombin mutation G20210 A, increased AT-III antigen activity level, elevated fasting homocysteine levels from MTHFR mutation (Methalenetetrahydrofolate Reductase), reduced protein C and S activity levels (C=serine protease, destroys activated Factors 5, 8 , factor S is cofactor). Additional features, such as obesity, inactivity, smoking, mechanical heart valve, atrial fibrillation, trauma or major surgery also increase risk.
What is the major difference in immune pathogenesis between lupus and Sjogren’s syndrome?
Both show similar autoantibodies but lupus tends to develop immune complex disease whereas in Sjogren’s syndrome damage occurs by lymphocytic infiltration.
How well does plasmapheresis work in catastrophic antiphospholipid antibody syndrome (CAPS)?
Plasmapheresis combined with intravenous steroids and heparin has been used to treat catastrophic APS since 1988 and seems to increase response rates from 50% to 70%. There are no controlled trials and most patients were also treated with intravenous steroids, anticoagulation, hydroxychloroquine, and aspirin.
What are the Sidney criteria (revised Sapporo 2006) for diagnosing antiphospholipid antibody syndrome?
At least 1 event providing clinical evidence of the deep vein thrombosis, embolic phenomena, and/or biopsy evidence of thrombosis must be present. Significantly elevated ACA or B2 glycoprotein antibodies or lupus anticoagulant with prolonged PTT uncorrected by normal plasma, must also be present. Diagnostic pregnancy problems include loss of three or more embryonic pregnancies (less than 10 weeks gestation), loss of morphologically norma fetus after 10 weeks, or premature birth before 34 weeks due to the eclampsia, preeclampsia, or placental insufficiency.
What additional causes for thromboembolism occur aside from antiphospholipid antibody syndrome.
Arterial thrombosis/embolism may be caused by - 1) blood plasma problems: (TTP/HUS), Hellp syndrome, sepsis with multiorgan failure, nephrotic syndrome, hyper viscosity, decompression sickness, dysfibrinogenemia, homocystinemia, atrial fibrillation. 2) blood cell disorders: sickle cell disease, platelet dysfunction-disseminated intravascular coagulation,, myeloproliferative disorders. 3) vascular disorders: endocarditis, atherosclerosis, cholesterol emboli, paradoxical embolism, polyarteritis nodosa, ANCA positive vasculitis. Medications -heparin, phenothiazines, hydralazine, procainamide, phenytoin.
What are some suspicious features of antiphospholipid syndrome aside from the diagnostic criteria?
Non-criteria clinical findings include heart valve disease, livedo reticularis, nephropathy, and neurological manifestations. Non-criteria laboratory findings include thrombocytopenia, antibody titers < 99 percentile but still positive, or IGA anti-cardiolipin or anti-beta-2 glycoprotein antibodies. Blood for all tests save anticardiolipin and antiphopholipid antibodies must be collected as platelet free as possible and prior to use of warfarin or low molecular weight or unfractionated heparin.
What are the 11 2012 SLICC (Systemic lupus international collaborating clinics) clinical criteria (+ CBC, U/A) for SLE?
1) acute cutaneous lupus: malar rash, bullous lupus, macular papular lupus rash, photosensitive lupus rash, subacute cutaneous lupus. 2) chronic cutaneous lupus: chronic discoid rash, lupus panniculitis, chilblains lupus, discoid-lichen planus overlap. 3) Nonscarring alopecia 4) Oral or nasal ulcers observed by physician. Palate, buccal, tongue. 5) arthritis: nonerosive two or more peripheral joints, tenderness, swelling or effusion, or tenderness in 2 or more joints and 30 minutes of morning stiffness. 6) Serositis: pleuritis; history pleuritic pain for one day or rub heard by physician or pleural effusion or pericarditis by EKG, rub or pericardial effusion. 7) Renal disorder: proteinuria > 0.5 gm/day or > 3+, or cellular casts red hemoglobin granular tubular or mixed 8) neurologic disorder: seizures, psychosis, myelitis, peripheral or cranial neuropathy, acute confusional state 9) Hemolytic anemia with reticulocytosis 10) leukopenia < 4k, on two or more occasions or lymphopenia < 1.0 k on two or more occasions 11) thrombocytopenia < 100 k.
What are the 6 immunologic 2012 SLICC (Systemic lupus international collaborating clinics) criteria for the diagnosis of SLE?
Immunologic Criteria 1) ANA 2) dsDNA 3) anti-Sm 4) antiphospholipid (medium or high titer IgA, IgM, IgG aCL, abnormal anti-beta 2-glycoprotein IgA, IgM, IgG , or FPTSS with negative ftaABS. 5) Low complement C3, C4, or CH50 6) direct Coombs test in the absence of hemolytic anemia
What lupus autoantibodies appear after the ANA along with clinical lupus?
Anti-dsDNA, and anti-RNP. Other antibodies such as fluorescent ANA and SSA appear years before clinical SLE.
What anticoagulation program is appropriate for patients with antiphospholipid antibodies?
In patients with definite antiphospholipid antibody syndrome and symptomatic venous thrombosis, then heparinization followed by lifelong oral anticoagulation is appropriate. Patients after their first venous event with minimal titers of phospholipid antibodies or other causes for venous thrombosis, then anticoagulation may be stopped after 3 to 6 months. Patients with SLE or related autoimmune syndrome, but no venous thrombosis, low-dose aspirin may be appropriate. Patients with SLE should be treated with hydroxychloroquine.
