Faculty Bibliography

Background/Purpose: Thrombocytopenia is a common feature of both systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) and in the former most frequently results from antiplatelet antibodies (i.e., AITP) or aPL antibodies. Patients with AITP paradoxically have an increased risk of thrombosis and it has been speculated that this can result from co-presence of aPL. Primary APS is associated with both thrombosis and thrombocytopenia. We assessed whether there was an association between a history of thrombocytopenia and the prevalence of a thrombotic event in a large, multiethnic cohort of SLE patients. Methods: We analyzed the NYU SLE SAMPLE registry, consisting of patients fulfilling ACR and/or SLICC criteria for SLE. We identified 105 patients whose SLE criteria included the presence of one or more of the following aPL antibodies: lupus anticoagulant, IgG or IgM anti-beta2-glycoprotein-I, and/or IgG or IgM anticardiolipin antibodies; and determined whether these patients had thrombocytopenia (<100,000/muL) recorded among their SLE classification criteria. We reviewed each patient's medical record to identify the prevalence of arterial or venous thrombosis (defined as DVT, PE, stroke, arterial occlusion with gangrene or amputation), and/or obstetric events. We compared the prevalence of thrombotic events in SLE patients with and without history of thrombocytopenia. Results: The NYU SLE SAMPLE currently includes 612 patients (90% female, mean age 43.0+/-0.9 years, and mean age of 41.0+/-0.3 years in the males); 54% of the subjects were Caucasian, 31% African American, 15% Asian, 30% Hispanic White, and 5% Hispanic Black: 17% had aPL antibodies, of whom 89% were female and 11% male (mean age 43.0+/-0.2 years, 56% Caucasian, 33% African American, and 11% Asian, 24% Hispanic white and 4% Hispanic Black). The total numbers of patients with thrombotic events were 45 (43%), with 5/21 (23%) in the SLE patients with aPL and prior history of thrombocytopenia and 40/84 (47%; p=0.042) in the patients without thrombocytopenia. The most common thrombotic event was DVT followed by stroke. Conclusion: The prevalence of aPL in the NYU SLE registry was 17%, and adverse thrombotic events were less common in the patients with prior history of thrombocytopenia (5/21, 23%) as compared to those without (40/84, 47%). This unexpected finding could be explained by protective benefit of anti-platelet antibodies when co-occur with aPL in SLE, or less thrombogenic aPL in SLE when there is concomitant thrombocytopenia. Additionally, our data suggest that there might be different consequences of aPL between primary APS patients and SLE patients with aPL

Background/Purpose: Few studies have analyzed the risk factors for thrombosis in Systemic Lupus Erythematosus (SLE) patients with antiphospholipid antibodies (aPL) and most had small sample sizes and homogenous patient populations. We examined whether a history of nephritis is an additional risk factor for thrombosis on a large multi-ethnic SLE cohort database. Methods: The NYU SLE SAMPLE biorepository and registry was initiated in September 2013 and includes 612 patients fulfilling ACR and/or SLICC criteria for SLE. Within SAMPLE, we identified patients with a positive aPL test (lupus anticoagulant, IgG or IgM anti-beta2- glycoprotein-I antibodies and/or IgG or IgM anticardiolipin antibodies) and determined if these patients had also ever fulfilled nephritis criteria. We reviewed each patient's medical record for presence/absence of venous and arterial thrombosis, and obstetric events as well as the non-criteria manifestations such as thrombocytopenia or valvulitis. We compared the prevalence of antiphospholipid syndrome (APS) manifestations in SLE patients with and without a history of lupus nephritis. Results: Of the initial 612 SLE patients (90% female; mean age 43.0+/-0.9 years), 54% were Caucasian, 31% African American, 15% Asian; 30% Hispanic white, and 5% Hispanic Black. Of the 612 patients, 105 had aPL, including 93 females and 12 males (mean age 43.0+/-0.2 years), 56% Caucasian, 33% African American, 11% Asian, 24% Hispanic white and 4% Hispanic Black. The total number of patients with thrombotic events was 45/105 (43%), including 26/43 (60%) in the nephritis subset and 19/62 (30%) (p=0.04) among patients without prior renal involvement. The most common thrombotic event was deep vein thrombosis (DVT) followed by stroke. Conclusion: The prevalence of APS criteria in the NYU SLE SAMPLE was 17%. Within this group, adverse events were more common among the patients with, versus without, a prior history of renal involvement (60% vs 30%). It remains uncertain if this association can be explained by, for example, by the presence of other accompanying findings that distinguish nephritis from non-nephritis SLE (e.g. anti-dsDNA, complement consumption) or drug treatment. This observation provides further support for the universal use of hydroxychloroquine in SLE, especially in those with current or previous nephritis and suggests that event-free aPL positive patients with a prior history of nephritis may be at increased risk for future thrombosis. Further studies are needed to determine whether such patients could benefit from prophylaxis with low-dose aspirin, statins or even other mild anti-thrombotic agents

Background/Purpose: Current ACR and EULAR evidence based guidelines provide recommendations for therapeutic choices to induce and maintain remission of lupus nephritis, however, the appropriate duration of maintenance treatment remains unclear. Data from the ALMS, MAINTAIN, and NIH-funded clinical trials in support of duration greater than three years is absent. In an effort to balance drug toxicities with the desire to prevent late disease recurrence some authors recommend maintenance therapy for as long as five years. There is an active NIH sponsored clinical trial for randomization of MMF maintenance withdrawal in SLE patients in remission, however, these results are not yet available. We analyzed the prevalence of renal flare after MMF maintenance therapy withdrawal in NYU's large, multi-ethnic cohort of SLE patients. Methods: We queried the NYU SAMPLE Lupus Registry and biorepository to identify SLE nephritis patients with complete response who experienced renal flare within 12 months of discontinuing maintenance MMF therapy. The NYU SLE SAMPLE registry was initiated in September 2013 and includes 612 patients fulfilling ACR and/or SLICC criteria for SLE of which 42% have clinical nephritis. Results: The NYU SAMPLE registry has 612 SLE patients (90% female; mean age 43.0+/-0.9 years), 54% Caucasian, 31% African American, 15% Asian; 30% Hispanic white, 5% Hispanic Black and 256 patients (42%) have nephritis. Of the 256 SLE nephritis we identified four patients with renal relapse within 12 months of MMF withdrawal summarized in Table 1. Table 1. Characteristics of patients with renal flare after MMF maintenance treatment withdrawal Conclusion: In the two year period between 3/2014 and 3/2016 we identified 4 patients with a renal relapse within 12 months of maintenance therapy withdrawal. All of the patients were on MMF for maintenance and for a duration >4 years of treatment. Based on this experience we recommend that maintenance of SLE GN with MMF absent contraindication should be at least 5 years and in the interval after withdrawal at any juncture careful monitoring and laboratory studies should be performed no less often than every 3 months for at least 2 years from time of maintenance therapy withdrawal. The occurrence of a renal flare during tapering, also highlights the need for guidelines regarding the rate of withdrawal. Determining risk factors for renal flare after maintenance withdrawal is necessary to facilitate clinicians identifying candidates for discontinuations or instances when to exercise caution.(Figure Presented)

Background/Objective: Thrombocytopenia is a common feature of both SLE and antiphospholipid syndrome (APS) and in former most frequently results from antiplatelet antibodies (ie AITP) or antiphospholipid antibodies (aPL). Patients with AITP paradoxically have an increased risk of thrombosis and it has been speculated that this can result from co-presence of aPL. Primary APS is associated with both thrombosis and thrombocytopenia. We assessed whether there was an association between a history of thrombocytopenia and prevalence of a thrombotic event in a large, multiethnic cohort of SLE patients. Methods: We analyzed the NYU SLE SAMPLE Registry, consisting of patients fulfilling ACR and/or SLICC criteria for SLE. We identified 105 patients whose SLE criteria included the presence of one or more of the following APLS antibodies: lupus anticoagulant; IgG or IgM anti-beta2-glycoprotein-I; IgG or IgM anticardiolipin antibodies, and determined whether these patients had thrombocytopenia among their SLE classification criteria (<100,000/muL). We reviewed each patient's medical record to identify the prevalence of thrombosis (defined as DVT, PE, CVA, arterial occlusion with gangrene or amputation), and/or obstetric events. We compared the prevalence of thrombotic events in SLE patients with and without history of thrombocytopenia. Results The NYU SLE SAMPLE currently includes 612 patients (90% female, mean age 43.0+/-0.9 years, and 10% men, mean age 41.0+/-0.3 years). 54% of subjects were white, 31% African American, and 15% Asian. 30% were Hispanic White, and 5% Hispanic Black. 17% had aPL, of whom 89% were female and 11% male (mean age 43.0+/-0.2 years, 56% Caucasian, 33% African American, and 11% Asian). 24% were Hispanic white and 4% Hispanic Black. The total numbers of patients with thrombotic events were 45 (43%), with 5/21 (23%) in the SLE patients with aPL and prior history of thrombocytopenia and 40/ 84 (47%) (p=0.042) in the patients without thrombocytopenia. The most common thrombotic event was DVT followed by CVA. Conclusion The prevalence of aPL in the NYU SLE registry was 17%, and adverse thrombotic events were less common in the patients with prior history of thrombocytopenia (5/21, 23%) as compared to those without (40/84, 47%). This unexpected finding could be explained by protective benefit of antiplatelet antibodies when co-occur with aPL in SLE or less thrombogenic aPL in SLE when produces thrombocytopenia. Additionally, our data suggest that there might be different consequences of aPL between primary APS patients and SLE patients with aPL

Background/Objective: Few studies have analyzed the risk factors for thrombosis in SLE patients with antiphospholipid antibodies and most had small sample sizes and homogenous patient populations. We examined whether a history of nephritis is a risk factor for thrombosis using a large multi-ethnic SLE cohort. Methods: The NYU SLE SAMPLE Biorepository and Registry was initiated in September 2013 and includes 612 patients fulfilling ACR and/or SLICC criteria for SLE. Within SAMPLE, we identified patients with a positive test for antiphospholipid antibodies (aPL) (lupus anticoagulant, IgG or IgM anti-beta2-glycoprotein-I antibodies, IgG or IgM anticardiolipin antibodies) and determined if these patients had also ever fulfilled nephritis criteria. We reviewed each patient's medical record for presence/absence of thrombosis (DVT, PE, CVA, arterial occlusion with gangrene or amputation), and obstetric events as well as the noncriteria manifestations thrombocytopenia or valvulitis. We compared the prevalence of APLS manifestations in SLE patients with and without history of lupus nephritis. Results: Of the initial 612 SLE patients, 90% were female (mean age 43.0+/-0.9 years), and 10% were male (mean age 41.0+/-0.3 years). 54% were white, 31% African American, and 15% Asian; 30% were Hispanic white, and 5% Hispanic Black. 105 of the 612 patients had aPL, including 93 females and 12 males (mean age 43.0+/-0.2 years, 56% Caucasian, 33% African American, and 11% Asian). 24% were Hispanic white and 4% Hispanic Black. The total number of patients with thrombotic events was 45/105 (43%), including 26/43 (60%) in the nephritis subset and 19/62 (30%) (p: 0.04) among patients without prior renal involvement. The most common thrombotic event was DVT followed by CVA. Conclusion: The prevalence of aPL criteria in NYU SLE SAMPLE was 17%. Within this group, adverse events were more common among the patients with, versus without, prior history of renal involvement (60% vs 30%). It remains uncertain if association is explained by different accompanying antibodies that distinguish nephritis from non-nephritis SLE, e.g., dsDNA, complement, or drug treatment. This observation provides further support for universal use of hydroxychloroquine in SLE especially in setting of nephritis and suggests that event-free aPL positive patients with prior history of nephritis may be at increased risk for future thrombosis. Further studies are needed to determine whether such patients could benefit from prophylaxis with aspirin or other mild antithrombotic agents

Background/Objective: We and others have suggested that complement activation can serve as an initiating signal that increases the thrombosis risk in SLE patients with antiphospholipid antibodies (aPL). Generation of complement activation products can result in proinflammatory and/or prothrombotic responses providing a permissive environment for the pathological effects of antibodies to negatively charged phospholipid protein complexes. Methods: We analyzed the NYU SLE SAMPLE Biorepository initiated in September 2013, which consists of 599 patients fulfilling ACR and/or SLICC criteria for systemic lupus erythematosus. We identified 98 patients whose criteria included the presence of one or more for the following aPL: lupus anticoagulant, IgG or IgM anti-beta2- glycoprotein-I, or IgG or IgM anticardiolipin antibodies and determined if these patients received SLEDAI points for hypocomplementemia during any encounter. We then reviewed each patient's medical record to identify the prevalence of thrombosis defined as DVT, PE, CVA, arterial occlusion with gangrene or amputation, and obstetric events as well as noncriteria manifestation of thrombocytopenia or valvulitis. We then compared the prevalence of these APLS manifestations in the SLE patients with and without evidence of complement activation. Results: The NYU SLE SAMPLE biorepository includes 599 patients (90% female, mean age 43.0+/-.9, and 10 % men, mean age 41.0+/-.3, 54% Caucasian, 31% African American, 15% Asian, 30% Hispanic White, and 5% Hispanic Black). 98 of the 599 SLE patients had aPL, 86 female and 12 male (mean age 43.0+/-.2, 56% Caucasian, 33% African American, and 11% Asian). 24 % were Hispanic white and 4% Hispanic Black. The total number of patients with adverse events was 54 of 98 (55%) with 33/50 (66%) in the SLE patients with aPL and evidence of hypocomplementemia and 21/48 (43%) (p=0.04) in the patients without evidence of hypocomplementemia. The most common thrombotic event was DVT followed by CVA. Conclusions: The prevalence of aPL as a criteria in the NYU SLE registry is 98 of 599, and adverse events were more common in the patients with evidence of hypocomplementemia (33/50, 66%) as compared to the patients without complement activation (21/48, 43%). These findings can inform decisions regarding which patient subsets that may benefit from the prophylactic use of low-dose aspirin for primary prevention in asymptomatic lupus patients. Moreover, future clinical trials should be stratified on the basis of complement consumption to be sure that equal numbers of these patients appear in both the experimental and comparator treatment arms. Finally, future prospective studies should explore the interaction between complement activation products, platelets, neutrophils, mononuclear cells, endothelial cells, coagulation cascade in the adverse events that constitute antiphospholipid syndrome

Background/Objective: The spectrum of the vascular pathology affecting SLE patients with secondary APS includes vasculopathy with endothelial cell hyperplasia as in APS nephropathy. Previous studies established a role for endothelial cell activation via the mammalian target of rapamycin (mTORC) but were limited to primary APS patients and the IgG fractions. We extend this finding by studying SLE patients with secondary APS and demonstrate this activity resides in both IgG and IgA fractions. Methods: Endothelial cell phenotypes were assessed using an immunofluorescent assay to report the mTORC biomarker, phospho-S6 ribosomal protein (S6RP) using the human microvascular cell line (HMEC1) in the presence and absence of purified human IgG, IgGFab2, and IgA with or without LY294002, a mTORC inhibitor. We studied eight SLE patients with secondary APS (mean age 46.8+/-.3, 89 % female and 67% white), four disease controls that were either SLE without APS or asymptomatic anti-Ro positive, and three normal controls. Purified IgG and IgA fractions were used as follows: SLE patients four IgG and IgA, three IgG and I IgA, four disease controls two IgG and IgA and two IgG, and controls two IgG and IgA. HMEC1 were serum starved (2 hr), and preincubated with beta2 glycoprotein I (5 ug/mL, 1 hour) followed by a five min exposure to test conditions. Fixed cells were acetone permeabilized and stained using an anti-phospho - S6RP (anti-mouse IgG TRITC) and counterstained with Hoechst 33342. Immunofluorescence was reported using both intensity (1-3+) and a staining scale reflecting % positive cells (3 fields) with 1, <10%; 2, 10-30%; 3, 40-50%; and 4>50%. Results: The phenotype of the endothelial cells which were coincubated with the IgG fractions of 3 (of 8) patients were diffusely positive for phospho- S6RP which was substantially attenuated by co-incubation with LY294002 (1+, 1 % positive cells). In addition, treatment of endothelial cells with IgA fractions from the same three individuals resulted in an increase of phosphorylation of S6RP in microvascular endothelial cells, suggesting the importance of both IgG and IgA APS isotypes. For the total group of eight SLE patients with APS antibodies however there was no association with APS titers and the ability to elicit the biomarker in HMEC1. The expression of phospho- S6RP by HMEC1 were within the ranges that is reported for no treatment (1+, <3 to report % positive cells) for IgG fractions isolated from both disease and healthy controls, Fab2 from a disease control and a control IgA. Conclusions: We report the novel finding that both IgG and IgA fractions from SLE patients with secondary APS activate endothelial cells via the mTORC pathway as demonstrated by S6RP phosphorylation. Future studies will explore these findings using Western blot analysis and explore endothelial cell gene expression for ICAM-1, E-selectin, NOS-2 and tissue factor in an effort to determine potential role of this pathway in the full spectrum of vascular pathology that accompanies APS in SLE

BACKGROUND: Glucocorticoid-induced osteoporosis (GIO) is the most common secondary form of osteoporosis, and glucocorticoid users are at increased risk for fracture compared with nonusers. There is no established relationship between bone mineral density (BMD) and fracture risk in GIO. We used 3 Tesla (T) MRI to investigate how proximal femur microarchitecture is altered in subjects with GIO. METHODS: This study had institutional review board approval. We recruited 6 subjects with long-term (> 1 year) glucocorticoid use (median age = 52.5 (39.2-58.7) years) and 6 controls (median age = 65.5 [62-75.5] years). For the nondominant hip, all subjects underwent dual-energy x-ray absorptiometry (DXA) to assess BMD and 3T magnetic resonance imaging (MRI, 3D FLASH) to assess metrics of bone microarchitecture and strength. RESULTS: Compared with controls, glucocorticoid users demonstrated lower femoral neck trabecular number (-50.3%, 1.12 [0.84-1.54] mm(-1) versus 2.27 [1.88-2.73] mm(-1) , P = 0.02), plate-to-rod ratio (-20.1%, 1.48 [1.39-1.71] versus 1.86 [1.76-2.20], P = 0.03), and elastic modulus (-64.8% to -74.8%, 1.54 [1.22-3.19] GPa to 2.31 [1.87-4.44] GPa versus 6.15 [5.00-7.09] GPa to 6.59 [5.58-7.31] GPa, P < 0.05), and higher femoral neck trabecular separation (+192%, 0.705 [0.462-1.00] mm versus 0.241 [0.194-0.327] mm, P = 0.02). There were no differences in femoral neck trabecular thickness (-2.7%, 0.193 [0.184-0.217] mm versus 0.199 [0.179-0.210] mm, P = 0.94) or femoral neck BMD T-scores (+20.7%, -2.1 [-2.8 to -1.4] versus -2.6 [-3.3 to -2.5], P = 0.24) between groups. CONCLUSION: The 3T MRI can potentially detect detrimental changes in proximal femur microarchitecture and strength in long-term glucocorticoid users. J. MAGN. RESON. IMAGING 2015;42:1489-1496.