Faculty Bibliography

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.

Background Granulomatosis with polyangiitis (GPA) relapse can complicate the differential diagnosis of pulmonary lesions. Case Report A 70-year-old male smoker with GPA and emphysema presented with dyspnea, dry cough, and a right upper lobe pulmonary ground-glass opacity that persisted despite antibiotics. A trans-bronchial biopsy did not reveal active vasculitis, malignancy, or infection. He was treated for presumed GPA relapse based on pulmonary manifestations, renal failure, and elevated PR3-ANCA. Later, hematuria led to the cystoscopic discovery of a bladder wall lesion, which was diagnosed as micropapillary urothelial carcinoma not involving the muscularis propria. The patient developed an increasing pulmonary infiltrate with a new solid component, satellite lesions, and regional lymphadenopathy. A right upper lobe wedge resection showed metastatic urothelial carcinoma. Conclusions The simultaneous presentation of a pulmonary lesion and GPA relapse is a diagnostic challenge. The differential diagnosis should include the rare possibility of metastatic urothelial carcinoma, regardless of how the lesion appears radiographically.

BACKGROUND: Subarachnoid hemorrhage (SAH) due to intracranial aneurysm rupture is a major neurosurgical emergency associated with significant morbidity and mortality. Rapid aneurysm growth is associated with rupture. Systemic lupus erythematosus (SLE) is a multi-system autoimmune disorder whose complications can include cerebral vasculitis and vasculopathy. Intracranial aneurysms are not known to occur more frequently in SLE patients than the general population; however, aneurysm growth rates have not been studied in SLE. CASE DESCRIPTION: We present a 43-year-old female with SLE on prednisone, hydroxychloroquine, and azathioprine with moderate disease activity who presented with severe, acute-onset headache and was found to have Hunt and Hess grade II SAH due to rupture of an 8 mm saccular anterior communicating artery (ACoA) aneurysm. The patient developed severe vasospasm, re-ruptured, and was taken for angiography and embolization, which was challenging due to a high degree of vasospasm and arterial stenosis. Review of imaging from less than 2 years prior demonstrated a normal ACoA complex without evidence of an aneurysm. CONCLUSION: We review the literature and discuss the risk factors and pathophysiology of rapid aneurysm growth and rupture, as well as the pathologic vascular changes associated with SLE. Although SLE patients do not develop intracranial aneurysm at an increased rate, these changes may predispose them to higher incidence of growth and rupture. This possibility-coupled with increased morbidity and mortality of SAH in SLE-suggests that SAH should be considered in SLE patients presenting with headache, and advocates for more aggressive treatment of SLE patients with unruptured aneurysms.

Anal squamous cell carcinoma is a potentially fatal disease. Human papilloma virus (HPV) is the most common sexually transmitted disease worldwide and is responsible for almost all cases of anal cancer. Immunocompromised patients are at increased risk of developing anal dysplasia and malignancies. A lack of awareness of HPV-associated anal malignancies in the immunocompromised may lead to a delay in diagnosis and confer a poor prognosis.

This 2013 update on the treatment of systemic lupus erythrematosus provides rationale for universal use of antimalarials even absent skin or joint manifestations, but chiefly focuses on the management options for refractory cutaneous, articular, and renal disease and current status of biologics; both FDA approved belimumab and off-label infliximab, rituximab, abatacept, and tociluzimab. A discussion of antiphospholipid syndrome secondary to lupus, specifically use of aspirin for asymptomatic patients, suggestions for catastrophic antibody syndrome, and potential roles for rituximab and eculizumab are provided. This review is a companion to an article published in this journal last year and in combination provides recommendations for standard care in routine cases of lupus as well as for the problematic, intractable patient.

Pseudo-pseudo Meigs' syndrome (PPMS) is a rare manifestation of patients with systemic lupus erythematosus (SLE), defined by the presence of ascites, pleural effusions and an elevated CA-125 level. We describe a patient with longstanding lupus who presented with localized lymphadenopathy and subsequently developed massive chylous ascites with marked hypoalbuminemia. A brief historical overview of Meigs' syndrome and related entities is presented, along with a discussion of the differential diagnosis of hypoalbuminemia and ascites in an SLE patient. In addition, we speculate on the optimal therapeutic intervention in such a patient.

The Lupus Foundation of America (LFA) convened an international working group to obtain a consensus definition of disease flare in lupus. With help from the Paediatric Rheumatology International Trials Organization (PRINTO), two web-based Delphi surveys of physicians were conducted. Subsequently, the LFA held a second consensus conference followed by a third Delphi survey to reach a community-wide agreement for flare definition. Sixty-nine of the 120 (57.5%) polled physicians responded to the first survey. Fifty-nine of the responses were available to draft 12 preliminary statements, which were circulated in the second survey. Eighty-seven of 118 (74%) physicians completed the second survey, with an agreement of 70% for 9/12 (75%) statements. During the second conference, three alternative flare definitions were consolidated and sent back to the international community. One hundred and sixteen of 146 (79.5%) responded, with agreement by 71/116 (61%) for the following definition: 'A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment.' The LFA proposes this definition for lupus flare on the basis of its high face validity