Faculty Bibliography

The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histologic differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.

OBJECTIVE:To evaluate subsequent rate of thrombosis among obstetric antiphospholipid syndrome (Ob-APS) women in a multicenter database of antiphospholipid antibody (aPL)-positive patients; and clinical utility of adjusted Global Antiphospholipid Syndrome Score (aGAPSS), a validated tool to assess the likelihood of developing new thrombosis, in this group of patients. DESIGN/METHODS:Retrospective study. SETTING/METHODS:APS Alliance For Clinical Trials & International Networking (APS ACTION) Clinical Database And Repository. POPULATION/METHODS:Women with Ob-APS. METHODS:Comparison of clinical and laboratory characteristics; measurement of aGAPSS of Ob-APS women with or without thrombosis after initial pregnancy morbidity (PM). MAIN OUTCOME MEASURES/METHODS:Risk factors for thrombosis, aGAPSS. RESULTS:Of 550 patients, 126 had Ob-APS; 74/126 (59%) presented thrombosis, and 47 (63%) of them developed thrombosis after initial PM, in a mean time of 7.6 ± 8.2 years (4.9/100 patient years). Younger age of Ob-APS, additional cardiovascular risk factors, superficial vein thrombosis, heart valve disease, and multiple aPL positivity increased the risk of first thrombosis after PM. Women with thrombosis after PM had higher aGAPSS compared to those with Ob-APS alone ([median 11.5 [4-16] vs 9 [4-13], P = 0.0089]). CONCLUSION/CONCLUSIONS:Based on retrospective analysis of our multicenter aPL database, 63% of Ob-APS women developed thrombosis after initial obstetric morbidity; additional thrombosis risk factors, selected clinical manifestations, and high-risk aPL profile increased risk. Women with subsequent thrombosis after Ob-APS had higher aGAPSS score at registry entry. We believe that aGAPSS is a valid tool to improve risk stratification in aPL-positive women. There was no funding for this study.

Background Autoantibody and laboratory testing is essential for SLE diagnosis. ANA by indirect immunofluorescence (ANA IIF) remains the gold standard to screen for lupus and studies demonstrate preclinical phase during which autoantibodies accumulate. Prevalence of ANA IIF alone without more specific autoantibodies and the accompanying clinical phenotype of these patients uncertain. Methods Queried 602 patients in the NYU Lupus Registry with 4 or more ACR or SLICC criteria as adjudicated by the authors for prevalence of ANA IIF, dsDNA, Sm, Ro, La, RNP, aPL, C3, C4. Compared clinical features of isolated ANA (ANA IIF alone) with the ANA IIF plus one or more lupus associated abnormalities (ANA IIF +). Results 590/602 (98%) ANA IIF positive. 548/590 (93%) patients at least one of associated tests compared to only 42/ 590 (7%) ANA IIF alone. SLE nephritis significantly more prevalent in ANA IIF+254/548 (46%), compared to 13/42 (31%) recorded with renal criteria ANA IIF alone. ANA IIF +, 158/254 (62%) biopsy proven nephritis (LN), rather than relying on proteinuria for diagnosis, compared to 5/13 (38%) of ANA IIF alone biopsy proven LN. Remaining 8 ANA IIF alone, uPCR exceeded 0.5 g in 1 of 44 (2%) encounters. Low incidence of proteinuria explained by complete renal response or prior proteinuria misconstrued as evidence of LN. In comparison, uPCR >0.5 g was present in 694 of 1157 (60%) encounters in ANA IIF +, casting doubt on validity of LN diagnosis in 8 ANA IIF alone without biopsy. Leucopenia, lymphocytopenia, AITP, AIHA statistically less ANA IIF alone compared to ANA IIF + ; 24% vs 36%, 29% vs 40%, 7% vs 15% and 0% vs 7%, respectively. 42 patients with ANA IIF alone prevalence of potentially misattributed (e.g. not result of IMID) clinical criteria such as photosensitivity (64%) and malar rash (60%) greater compared to ANA IIF +, 38% and 44%, respectively. Prevalence oral ulcers, DLE, arthritis, serositis, seizures and psychosis equivalent in both. Conclusions ANA IIF alone rare and patients infrequently develop nephritis, leucopenia, lymphocytopenia, AITP, AIHA. In patients ANA IIF alone attribution of ACR/SLICC clinical criteria needs to be point of emphasis and unless biopsy proven, alternative explanation for proteinuria should be considered. Data argues inclusion criteria for clinical trials, rather than allowing ANA IIF alone or dsDNA, may need to require ANA IIF and at least one of the following (dsDNA, Sm, Ro, La, aPL, or hypocomplementemia) to avoid enrolling patients that do not have SLE

OBJECTIVE:Although systemic lupus erythematosus (SLE) is the most common autoimmune disease associated with antiphospholipid antibodies (aPL), limited data exist on the impact of SLE on the clinical phenotype of aPL-positive patients. The primary objective was to compare the clinical, laboratory, and treatment characteristics of aPL-positive patients with or without SLE. METHODS:A secure web-based data capture system stores patient demographics, and aPL-related clinical and laboratory characteristics. Inclusion criteria include aPL positivity according to the Updated Sapporo Classification Criteria. Patients fulfilling the SLE Classification Criteria and those with no other autoimmune diseases were included in the analysis. RESULTS:glycoprotein-I antibodies (aβ₂GPI), whereas the aPL only group had higher rates of cognitive dysfunction and IgG aβ₂GPI. The frequency of arterial and venous thromboses (including recurrent) as well as the pregnancy morbidity were similar between the groups. The prevalence of cardiovascular disease risk factors at the registry entry did not differ between the two groups, except current smoking, which was more frequent in aPL with SLE group. CONCLUSIONS:Although the frequencies of thrombosis and pregnancy morbidity are similar between aPL-positive patients with or without SLE, the diagnosis of SLE in persistently aPL-positive patients is associated with an increased frequency of thrombocytopenia, hemolytic anemia, low complements, and IgA aβ₂GPI positivity.

Objective/UNASSIGNED:Epidemiological data for primary discoid lupus erythematosus (pDLE) remain limited, particularly for racial/ethnic populations in the USA. The Manhattan Lupus Surveillance Program (MLSP) is a population-based retrospective registry of cases with SLE and related diseases including pDLE in Manhattan and was used to provide estimates of the prevalence and incidence of pDLE across major racial/ethnic populations. Methods/UNASSIGNED:MLSP cases were identified from rheumatologists, hospitals and population databases. Two case definitions were used for pDLE: the primary case definition which was any physician diagnosis found in the chart and a secondary case definition which was limited to cases diagnosed by a rheumatologist and/or dermatologist. Rates among Manhattan residents were age-adjusted, and capture-recapture analyses were conducted to assess case under-ascertainment. Results/UNASSIGNED:Based on the primary definition, age-adjusted overall prevalence and incidence rates of pDLE among Manhattan residents were 6.5 and 0.8 per 100 000 person-years, which increased to 9.0 and 1.3 after capture-recapture adjustment. Prevalence and incidence rates were approximately two and six times higher, respectively, among women compared with men (p<0.0001). Higher prevalence was also found among non-Latino blacks (23.5) and Latinos (8.2) compared with non-Latino whites (1.8) and non-Latino Asians (0.6) (p<0.0001). Incidence was highest among non-Latino blacks (2.4) compared with all other racial/ethnic groups. Similar relationships were observed for the secondary case definition. Conclusion/UNASSIGNED:Data from the MLSP provide epidemiological estimates for pDLE among the major racial/ethnic populations in the USA and reveal disparities in pDLE prevalence and incidence by sex and race/ethnicity among Manhattan residents.

Non-bacterial thrombotic endocarditis in antiphospholipid syndrome presents a management dilemma. Large mobile valvular lesions pose an increased risk of stroke and arterial embolization. However, surgical excision or valve replacement in such patients carries high morbidity and mortality, while anticoagulation alone has limited data. We describe two patients with antiphospholipid syndrome presenting with neurologic events and large non-bacterial aortic valve vegetations. Both patients were successfully managed with anticoagulation and demonstrated rapid dissolution of lesions without evidence of recurrent embolic events. We provide a literature review describing additional cases managed with anticoagulation with dissolution of valvular lesions over time. Our cases further support the efficacy and safety of anticoagulation in patients with antiphospholipid syndrome and non-bacterial thrombotic endocarditis in the context of arterial embolization.

OBJECTIVE:To study membrane attack complex in lupus nephritis as a potential biomarker for disease intensity and prognostic indicator for response to treatment. METHODS:Immunohistochemistry was performed using unconjugated, murine anti-human complement C9 on kidney biopsies from 30 SLE patients who fulfilled 4 ACR or SLICC criteria. Clinical parameters were assessed at time of biopsy, 6 and 12 months. RESULTS:30 renal biopsies were obtained from patients with Class II (2), III (5), IV (8), V (5), III+V (8) and IV+V (2). 13/30 (43.3%) biopsies stained positive for glomerular C9. Patients with positive C9 had significantly higher blood pressure, trend towards lower C3, and male gender. There was no significant difference for ISN/RPN class, activity or chronicity indices between C9 positive and negative groups. 5/11 (45.5%) patients positive for C9 did not respond to therapy at 6 months compared with 2/15 (13.3%) patients negative for C9. C9 positive patients were more likely to be a non-responder at 6 months (OR = 5.4, 95% CI: 0.8, 36.4) compared to C9 negative patients. After adjusting for systolic blood pressure, compliance to treatment and proteinuria in a multivariate logistic model, C9 positive patients remained more likely to be non-responders (OR = 4.6, 95% CI: 0.3, 70.9). CONCLUSION/CONCLUSIONS:This study suggests that MAC deposition measured as C9 staining may be a biomarker for more intense disease and poor response to treatment in lupus nephritis. MAC staining may be useful in routine studies of lupus biopsies and identify patients at risk for aggressive disease who may be candidates for novel therapies targeting terminal complement pathway.