Total cortical interstitial inflammation predicts chronic kidney disease progression in patients with lupus nephritis.

BACKGROUND: End-stage kidney disease (ESKD) from lupus nephritis (LN) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Kidney biopsy is the gold standard for diagnosis and prognostication of LN. While interstitial fibrosis and tubular atrophy (IFTA) predict progression to ESKD, the National Institutes of Health (NIH) classification of interstitial inflammation in unscarred cortical parenchyma is not predictive of chronic kidney disease (CKD) progression. The objective of this study was to determine whether total cortical interstitial inflammation that accounts for inflammation in the entire cortical parenchyma could predict CKD progression in patients with LN. Early identification of at-risk patients may improve outcomes. METHODS: This retrospective cohort study included 125 SLE patients with LN class III, IV, V or mixed (III/V, IV/V) on the index biopsy (2005-2018). Kidney biopsies were reviewed and assigned based on the 2018 NIH Activity Index (AI) and tubulointerstitial lesion categories. Total interstitial inflammation in the entire cortical parenchyma was graded as 0, 1, 2 or 3, corresponding to <10%, 10-25%, 26-50% and >50%, respectively, of the total cortical parenchyma containing an inflammatory infiltrate (similar to the definition used in the Banff total inflammation score). CKD progression was defined as an estimated glomerular filtration rate decrease of ≥30% within 5 years after the index biopsy. Kaplan-Meier survival curves and Cox proportional hazards models were performed to compare the two scoring systems, the total cortical intestinal inflammation score and the NIH interstitial inflammation score as predictors of CKD progression. RESULTS: Of 125 patients, 46 experienced CKD progression; 21 of 46 subsequently developed ESKD, 28 (22.4%) had moderate-severe total cortical interstitial inflammation and 8 (6.4%) had moderate-severe NIH interstitial inflammation. There were no differences in baseline characteristics between progressors and nonprogressors. Total cortical interstitial inflammation was associated with CKD progression in time-dependent analyses [hazard ratio 2.45 (95% confidence interval 1.2-4.97)] adjusted for age at biopsy, race, sex, LN class and hypertensive vascular change on kidney biopsy. The NIH interstitial inflammation was not associated with CKD progression. CONCLUSIONS: In contrast to the current NIH interstitial inflammation classification, accounting for interstitial inflammation in the entire cortical parenchyma allows identification of patients at risk for CKD progression in LN.

Systemic lupus Erythematosus activity and Hydroxychloroquine use before and after end-stage renal disease.

BACKGROUND: SLE manifestations after ESRD may be underdiagnosed and undertreated, contributing to increased morbidity and mortality. Whether specific symptoms persist after ESRD or a shift towards new manifestations occurs has not been extensively studied, especially in the non-Caucasian patients in the United States. In addition, hydroxychloroquine (HCQ) prescribing patterns post-ESRD have not been described. The objective of this study was to assess lupus activity and HCQ prescribing before and after ESRD development. Knowledge gained from this study may aid in the identification of SLE manifestations and improve medication management post-ESRD. METHODS: We performed a retrospective cohort study of SLE patients with incident ESRD between 2010 and 2017. SLE-related symptoms, serologic markers of disease activity, and medication use were collected from medical records before and after ESRD development. RESULTS: Fifty-nine patients were included in the study. Twenty-five (43%) patients had at least one clinical (non-renal) SLE manifestation documented within 12 months before ESRD. Of them, 11/25 (44%) continued to experience lupus symptoms post-ESRD; 9 patients without clinical or serological activity pre-ESRD developed new symptoms of active SLE. At the last documented visit post-ESRD, 42/59 (71%) patients had one or more clinical or serological markers of lupus activity; only 17/59 (29%) patients achieved clinical and serological remission. Thirty-three of 59 (56%) patients had an active HCQ prescription at the time of ESRD. Twenty-six of the 42 (62%) patients with active SLE manifestations post-ESRD were on HCQ. Patients who continued HCQ post-ESRD were more likely to be followed by a rheumatologist (26 [87%] vs 17 [61%], p = 0.024), had a higher frequency of documented arthritis (10 [32%] vs 1 [4%], p = 0.005), CNS manifestations (6 [20%] vs 1 [4%], p = 0.055), and concurrent immunosuppressive medication use (22 [71%] vs 12 [43%], p = 0.029). CONCLUSIONS: Lupus activity may persist after the development of ESRD. New onset arthritis, lupus-related rash, CNS manifestations, low complement and elevated anti-dsDNA may develop. HCQ may be underutilized in patients with evidence of active disease pre- and post ESRD. Careful clinical and serological monitoring for signs of active disease and frequent rheumatology follow up is advised in SLE patients both, pre and post-ESRD.

Association between antiphospholipid antibodies and all-cause mortality among end-stage renal disease patients with and without SLE: a retrospective cohort study.

OBJECTIVE: To investigate the association between the presence of aPL and/or LA and all-cause mortality among end-stage renal disease (ESRD) patients with and without SLE. METHODS: We included ESRD patients >18 years old followed at an urban tertiary care centre between 1 January 2006 and 31 January 2014 who had aPL measured at least once after initiating haemodialysis. All SLE patients met ACR/SLICC criteria. APL/LA+ was defined as aCL IgG or IgM >40 IU, anti-ß2glycoprotein1 IgG or IgM >40 IU or LA+. Deaths as at 31 January 2014 were captured in the linked National Death Index data. Time to death was defined from the first aPL measurement. RESULTS: We included 34 SLE ESRD and 64 non-SLE ESRD patients; 30 patients died during the study period. SLE ESRD patients were younger [40.4 (12.5) vs 51.9 (18.1) years, P = 0.001] and more were women (88.2% vs 54.7%, P < 0.001) vs non-SLE ESRD patients. The frequency of aPL/LA+ was 24% in SLE and 13% in non-SLE ESRD (P = 0.16). Median (inter-quartile range) follow-up time was 1.6 (0.3-3.5) years in SLE and 1.4 (0.4-3.2) years in non-SLE, P = 0.74. The adjusted hazard ratio (HR) for all-cause mortality for SLE patients who were aPL/LA+ vs aPL/LA- was 9.93 (95% CI 1.33, 74.19); the adjusted HR for non-SLE aPL/LA+ vs aPL/LA- was 0.77 (95% CI 0.14, 4.29). CONCLUSION: SLE ESRD patients with aPL/LA+ had higher all-cause mortality risk than SLE ESRD patients without these antibodies, while the effects of aPL/LA on mortality were comparable among non-SLE ESRD patients.

Factors Associated with Worsening Interstitial Fibrosis/Tubular Atrophy in Lupus Nephritis Patients Undergoing Repeat Kidney Biopsy.

Background: Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE). Interstitial fibrosis/tubular atrophy (IFTA) on kidney biopsies strongly predicts progression to end-stage renal disease. However, factors associated with progression of IFTA are not known. The objective of this study was to evaluate the demographic, clinical, and histopathological factors at the time of index kidney biopsies that are associated with worsening IFTA on repeat biopsies. Methods: Patients with LN Class I to V or mixed LN on index biopsies who underwent a clinically indicated repeat biopsy between 2004 and 2020 were identified. None-mild IFTA was defined as < 25% acreage of the interstitium affected by fibrosis and atrophy, and moderate-severe IFTA was defined as ≥ 25% of the interstitium affected. Patients with none-mild IFTA on index biopsies who progressed to moderate-severe IFTA on repeat biopsies were defined as progressors. Patients with none-mild IFTA on both biopsies were defined as non-progressors. Results: Seventy-two patients who underwent clinically indicated repeat kidney biopsies were included, and 35 (49%) were identified as progressors. Compared to non-progressors, progressors had a higher proportion of proliferative LN (20 [57%] vs. 6 [17%], p = 0.002) and crescents (9 [26%] vs. 3 [8%], p = 0.045) on index biopsies. There was no difference regarding the time to repeat biopsy or the baseline characteristics, including eGFR, presence of hypertension and diabetes, urine protein to creatinine ratio, or the initial treatments. Conclusions: Proliferative LN and the presence of crescents on index biopsies were associated with subsequent IFTA progression on repeat biopsies. This association indicates that glomerular damage is one of the major drivers of tubulointerstitial scarring in SLE. IFTA progression may, in turn, be the driving factor of poor treatment response and progression to chronic kidney disease.

Dendritic cells: an important link between antiphospholipid antibodies, endothelial dysfunction, and atherosclerosis in autoimmune and non-autoimmune diseases.

The presence of dendritic cells, antigen-presenting cells that link innate and adaptive immunity, is necessary to generate and maintain the production of antiphospholipid antibodies in response to exposed intracellular phospholipids on the outer surface of apoptotic cells. In turn, antiphospholipid antibodies enhance dendritic cell-induced inflammatory and proatherogenic responses in a number of conditions that are associated with accelerated atherosclerosis, including diabetes, chronic kidney disease, periodontal infections, and aging. While altering dendritic cells by modifying the ubiquitin-proteasome system enhances antiphospholipid antibody production and leads to development of accelerated atherosclerosis and autoimmune features, inducing tolerance by dendritic cell manipulation leads to decreased atherosclerosis and thrombosis. Therefore, further translational studies are needed to understand the interplay between dendritic cells and antiphospholipid antibodies, and to develop potential new therapies for antiphospholipid syndrome and atherosclerosis. Here we review current experimental and translational studies that have examined the role of dendritic cells in antiphospholipid antibody formation and in antiphospholipid-associated atherosclerosis and thrombosis.

Improving outcomes in patients with lupus and end-stage renal disease.

The development of lupus-related end-stage renal disease (ESRD) confers the highest mortality rates among individuals with lupus. Lupus-related ESRD is also associated with higher morbidity and mortality rates compared with non-lupus ESRD. We review the evidence that persistent lupus activity, hypercoagulability, and continuing immunosuppression may contribute to unfavorable outcomes in dialysis and renal transplantation among lupus patients. Robust epidemiologic studies are needed to develop individualized evidence-based approaches to treating lupus-related ESRD. In the meantime, managing lupus-related ESRD presents a significant challenge for clinicians and requires a team approach involving nephrologists and rheumatologists. Goals of therapy after developing ESRD should include continuing monitoring of lupus activity, minimizing corticosteroid exposure, and choosing the most appropriate renal replacement therapy based on patient's risk profile and quality-of-life considerations.

Association of Hydroxychloroquine Dose With Adverse Cardiac Events in Patients With Systemic Lupus Erythematosus.

OBJECTIVE: To determine whether hydroxychloroquine (HCQ) dose is associated with adverse cardiac outcomes in patients with systemic lupus erythematosus (SLE). METHODS: Patients with SLE taking HCQ and with ≥1 echocardiogram followed at a tertiary care center in the Bronx, New York between 2005 and 2021 were included. The HCQ weight-based dose at the HCQ start date was the main exposure of interest. The outcome was incident all-cause heart failure with reduced ejection fraction (HFrEF), life-threatening arrhythmia, or cardiac death. We used Fine-Gray regression models with death as a competing event to study the association of HCQ dose with the outcome. Due to a significant interaction between smoking and HCQ exposure, models were stratified by smoking status. Propensity score analysis was performed as a secondary analysis. RESULTS: Of 294 patients, 37 (13%) developed the outcome over a median follow-up time of 7.9 years (interquartile range [IQR] 4.2-12.3 years). In nonsmokers (n = 226), multivariable analysis adjusted for age, body mass index, hypertension, chronic kidney disease, diabetes mellitus, and thromboembolism showed that higher HCQ weight-based doses were not associated with an increased risk of the outcome (subdistribution hazard ratio [HR] 0.62 [IQR 0.41-0.92], P = 0.02). Similarly, higher baseline HCQ doses were not associated with a higher risk of the outcome among smokers (n = 68) (subdistribution HR 0.85 [IQR 0.53-1.34] per mg/kg, P = 0.48). Propensity score analysis showed comparable results. CONCLUSION: Higher HCQ doses were not associated with an increased risk of HFrEF, life-threatening arrhythmia, or cardiac death among patients with SLE and may decrease the risk among nonsmokers.

Urine Proteomics Link Complement Activation with Interstitial Fibrosis/Tubular Atrophy in Lupus Nephritis Patients.

BACKGROUND: Intrarenal complement activation has been implicated in the pathogenesis of tubulointerstitial fibrosis in lupus nephritis (LN) based on prior animal studies. The assembly of the membrane attack complex (MAC) by complement C5b to C9 on the cell membrane leads to cytotoxic pores and cell lysis, while CD59 inhibits MAC formation by preventing C9 from joining the complex. We hypothesize that complement activation and imbalance between complement activation and inhibition, as defined by increased production of individual complement components and uncontrolled MAC activation relative to CD59 inhibition, are associated with interstitial fibrosis and tubular atrophy (IFTA) in LN and correlate with the key mediators of kidney fibrosis- transforming growth factor receptors beta (TGFRß), platelet-derived growth factor beta (PDGFß) and platelet-derived growth factor receptor beta (PDGFRß). METHODS: We included urine samples from 46 adults and pediatric biopsy-proven lupus nephritis patients who underwent clinically indicated kidney biopsies between 2010 and 2019. We compared individual urinary complement components and the urinary C9-to-CD59 ratio between LN patients with moderate/severe IFTA and none/mild IFTA. IFTA was defined as none/mild (<25% of interstitium affected) versus moderate/severe (≥ 25% of interstitium affected). Proteomics analysis was performed using mass spectrometry (Orbitrap Fusion Lumos, Thermo Scientific) and processed by the Proteome Discoverer. Urinary complement proteins enriched in LN patients with moderate/severe IFTA were correlated with serum creatinine, TGFßR1, TGFßR2, PDGFß, and PDGFRß. RESULTS: Of the 46 LN patients included in the study, 41 (89.1%) were women, 20 (43.5%) self-identified as Hispanic or Latino, and 26 (56.5%) self-identified as Black or African American. Ten of the 46 (21.7%) LN patients had moderate/severe IFTA on kidney biopsy. LN patients with moderate/severe IFTA had an increased urinary C9-to-CD59 ratio [median 0.91 (0.83-1.05) vs 0.81 (0.76-0.91), p=0.01]. Urinary C3 and CFI levels in LN patients with moderate/severe IFTA were higher compared to those with none/mild IFTA [C3 median (IQR) 24.4(23.5-25.5) vs. 20.2 (18.5-22.2), p= 0.02], [CFI medium (IQR) 28.8 (21.8-30.6) vs. 20.4 (18.5-22.9), p=0.01]. Complement C9, CD59, C3 and CFI correlated with TGFßR1, PDGFß, and PDGFRß, while C9, CD59 and C3 correlated with TGFßR2. CONCLUSION: This study is one of the first to compare the urinary complement profile in LN patients with moderate/severe IFTA and none/mild IFTA in human tissues. This study identified C3, CFI, and C9-to-CD59 ratio as potential markers of tubulointerstitial fibrosis in LN.

Inhibition of the TWEAK/Fn14 pathway attenuates renal disease in nephrotoxic serum nephritis.

Previously it was shown that the TNF superfamily member TWEAK (TNFSF12) acts through its receptor, Fn14, to promote proinflammatory responses in kidney cells, including the production of MCP-1, RANTES, IP-10 and KC. In addition, the TWEAK/Fn14 pathway promotes mesangial cell proliferation, vascular cell activation, and renal cell death. To study the relevance of the TWEAK/Fn14 pathway in the pathogenesis of antibody-induced nephritis using the mouse model of nephrotoxic serum nephritis (NTN), we induced NTN by passive transfer of rabbit anti-glomerular antibodies into Fn14 knockout (KO) and wild type (WT) mice. Severe proteinuria as well as renal histopathology were induced in WT but not in Fn14 KO mice. Similarly, a pharmacologic approach of anti-TWEAK mAb administration into WT mice in the NTN model significantly ameliorated proteinuria and improved kidney histology. Anti-TWEAK treatment did not affect the generation of mouse anti-rabbit antibodies; however, within the kidney there was a significant decrease in glomerular immunoglobulin deposition, as well as macrophage infiltrates and tubulointerstitial fibrosis. The mechanism of action is most likely due to reductions in downstream targets of TWEAK/Fn14 signaling, including reduced renal expression of MCP-1, VCAM-1, IP-10, RANTES as well as Fn14 itself, and other molecular pathways associated with fibrosis in anti-TWEAK treated mice. Thus, TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the NTN model, apparently mediating a cascade of pathologic events locally in the kidney rather than by impacting the systemic immune response. Disrupting TWEAK/Fn14 interactions may be an innovative kidney-protective approach for the treatment of lupus nephritis and other antibody-induced renal diseases.

The constant region contributes to the antigenic specificity and renal pathogenicity of murine anti-DNA antibodies.

Affinity for DNA and cross-reactivity with renal antigens are associated with enhanced renal pathogenicity of lupus autoantibodies. In addition, certain IgG subclasses are enriched in nephritic kidneys, suggesting that isotype may determine the outcome of antibody binding to renal antigens. To investigate if the isotype of DNA antibodies affects renal pathogenicity by influencing antigen binding, we derived IgM, IgG1, IgG2b and IgG2a forms of the PL9-11 antibody (IgG3 anti-DNA) by in vitro class switching or PCR cloning. The affinity and specificity of PL9-11 antibodies for nuclear and renal antigens were analyzed using ELISA, Western blotting, surface plasmon resonance (SPR), binding to mesangial cells, and glomerular proteome arrays. Renal deposition and pathogenicity were assayed in mice injected with PL9-11 hybridomas. We found that PL9-11 and its isotype-switched variants had differential binding to DNA and chromatin (IgG3>IgG2a>IgG1>IgG2b>IgM) by direct and competition ELISA, and SPR. In contrast, in binding to laminin and collagen IV the IgG2a isotype actually had the highest affinity. Differences in affinity of PL9-11 antibodies for renal antigens were mirrored in analysis of specificity for glomeruli, and were associated with significant differences in renal pathogenicity in vivo and survival. Our novel findings indicate that the constant region plays an important role in the nephritogenicity of antibodies to DNA by affecting immunoglobulin affinity and specificity. Increased binding to multiple glomerular and/or nuclear antigens may contribute to the renal pathogenicity of anti-DNA antibodies of the IgG2a and IgG3 isotype. Finally, class switch recombination may be another mechanism by which B cell autoreactivity is generated.

Short- and Long-Term Progression of Kidney Involvement in Systemic Lupus Erythematosus Patients with Low-Grade Proteinuria.

BACKGROUND AND OBJECTIVES: Lupus nephritis remains a common cause of morbidity and mortality in systemic lupus erythematosus (SLE). Current guidelines recommend performing a kidney biopsy at a urine protein-creatinine ratio of ≥0.5 g/g. However, cross-sectional studies reported a high prevalence of active histologic lupus nephritis lesions, and even chronic irreversible scarring, in patients with low-grade proteinuria. This study was initiated to assess disease progression in patients with SLE and low-grade proteinuria to identify risk factors for progression to overt proteinuria suggestive of clinical lupus nephritis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with SLE who had an incident urinary protein-creatinine ratio of ≥0.2 and <0.5 g/g without known lupus nephritis were identified from the Einstein Rheumatic Disease Registry. Patients who developed a random urinary protein-creatinine ratio of ≥0.5 g/g with or without biopsy during the follow-up period were defined as "progressors." Patients who progressed to a urinary protein-creatinine ratio of ≥0.5 g/g within 2 years of developing a urinary protein-creatinine ratio of ≥0.2 and <0.5 g/g were defined as "fast progressors," a subgroup expected to benefit most from early biopsies and therapeutic interventions. RESULTS: Among 151 eligible patients with SLE and low-grade proteinuria at study entry, 76 (50%) progressed to a urinary protein-creatinine ratio of ≥0.5 g/g, of which 44 underwent a clinically indicated biopsy. The median (interquartile range) time from a urinary protein-creatinine ratio of ≥0.2 and <0.5 g/g to progression was 1.2 (0.3-3.0) years. Of the 20 biopsies performed in the first 2 years, 16 specimens showed active, treatable lupus nephritis. Low complement and shorter SLE duration at low-grade proteinuria onset were associated with progression to overt proteinuria across different analyses. Other associated factors included hypertension, diabetes mellitus, younger age, and the presence of hematuria. CONCLUSIONS: In this longitudinal cohort of patients with SLE and low-grade proteinuria at study entry, over half progressed to a urinary protein-creatinine ratio of ≥0.5 g/g in a short time period.

Prescribing Patterns of Hydroxychloroquine and Glucocorticoids Among Lupus Patients After New-Onset End-Stage Renal Disease.

OBJECTIVE: Optimal strategies for managing lupus medications after end-stage renal disease (ESRD) have not been addressed. The objective was to identify the current US-wide prescribing patterns of hydroxychloroquine (HCQ) and oral glucocorticoids (GS) among systemic lupus erythematosus (SLE) patients with incident ESRD enrolled in the US Renal Data System (USRDS) registry. METHODS: We identified incident ESRD patients age ≥18 years with SLE as a primary cause of ESRD between January 2006 and June 2013. Patients who were started on dialysis at ESRD onset and enrolled in Medicare Part D within 93 days as required by Medicare were included. RESULTS: Among the 2,654 new-onset ESRD patients with Part D, the median duration of follow-up was 761 days (interquartile range [IQR] 374-1,375). At baseline, 1,076 patients (41%) were not receiving HCQ or GS, 220 (8%) were prescribed HCQ alone, 509 (19%) were prescribed both HCQ and GS, and 849 (32%) were prescribed GS alone. Of the 1,983 patients who either never received or discontinued HCQ after ESRD onset, 667 (34%) continued GS to the end of the follow-up period. The median GS dose was lower for patients taking HCQ (14 mg [IQR 9-21]) compared to patients who were never prescribed HCQ (15 mg [IQR 9-27]) or patients who discontinued HCQ after ESRD (17 mg [IQR 10-27]; P = 0.001). CONCLUSION: Approximately one-third of patients with lupus nephritis and new-onset ESRD received GS monotherapy at high doses. As GS-related complications contribute to hospitalizations and deaths in SLE ESRD, changing these prescribing practices may improve morbidity and mortality outcomes.

Membrane attack complex (MAC) deposition in renal tubules is associated with interstitial fibrosis and tubular atrophy: a pilot study.

INTRODUCTION: Treatment failures for lupus nephritis (LN) are high with 10%-30% of patients progressing to end-stage renal disease (ESRD) within 10 years. Interstitial fibrosis/tubular atrophy (IFTA) is a predictor of progression to ESRD. Prior studies suggest that tubulointerstitial injury secondary to proteinuria in LN is mediated by complement activation in the tubules, specifically through the membrane attack complex (MAC). This study aimed to investigate the associations between tubular MAC deposition with IFTA and proteinuria. METHODS: In this cross-sectional study, LN kidney biopsies were assessed for MAC deposition by staining for Complement C9, a component of the MAC. Chromogenic immunohistochemistry was performed on paraffin-embedded human renal biopsy sections using unconjugated, murine anti-human Complement C9 (Hycult Biotech, clone X197). Tubular C9 staining intensity was analysed as present versus absent. IFTA was defined as minimal (<10%), mild (10%-24%), moderate (25%-50%) and severe (>50%). RESULTS: Renal biopsies from 30 patients with LN were studied. There were 24 (80%) female sex, mean age (SD) was 33 (12) years old and 23 (77%) had pure/mixed proliferative LN. Tubular C9 staining was present in 7 (23%) biopsies. 27 patients had minimal-to-mild IFTA and 3 patients had moderate IFTA. Among the C9 + patients, 3 (43%) had moderate IFTA as compared with none in the C9- group, p=0.009. C9 + patients had higher median (IQR) proteinuria as compared with C9- patients: 6.2 g (3.3-13.1) vs 2.4 g (1.3-4.6), p=0.001 at the time of biopsy. There was no difference in estimated glomerular filtration rate (eGFR) between the C9 + and C9- groups. CONCLUSION: This study demonstrated that tubular MAC deposition is associated with higher degree of IFTA and proteinuria, which are predictors of progression to ESRD. These results suggest that tubular MAC deposition may be useful in classification of LN. Understanding the role of complement in tubulointerstitial injury will also identify new avenues for LN treatment.

Association of Medication Access Difficulty and COVID-19-Related Distress With Disease Flares in Rheumatology Patients During the COVID-19 Pandemic.

OBJECTIVE: Due to concerns of infection and medication disruptions during the COVID-19 pandemic, rheumatology patients at the pandemic epicenter were at risk of distress and poor health outcomes. We sought to investigate medication disruptions and COVID-19-related distress in the Bronx, New York shortly after the peak of the pandemic and determine whether factors related to the pandemic were associated with flares, disease activity, and overall health. METHODS: In the month following the epidemic peak, we surveyed adult patients and parents of pediatric patients from rheumatology clinics in the Bronx regarding medication access, medication interruptions, COVID-19 infection, COVID-19 hospitalization, and COVID-19-related distress. We examined which factors were associated with patient-reported flares, disease activity, and overall health scores in regression models accounting for sociodemographic characteristics and rheumatologic disease type. RESULTS: Of the 1,692 patients and parents of pediatric patients that were contacted, 361 (21%) responded; 16% reported medication access difficulty, 14% reported medication interruptions, and 41% reported experiencing flare(s). In a multivariable logistic regression model, medication access difficulty was associated with increased odds of flare (odds ratio [OR] 4.0 [95% confidence interval (95% CI) 1.5, 10.4]; P = 0.005), as was high COVID-19-related distress (OR 2.4 [95% CI 1.2, 4.6]; P = 0.01). In multivariable linear regression models, medication access difficulty and high COVID-19-related distress were associated with worse disease activity scores, and high COVID-19-related distress was associated with worse health scores. CONCLUSION: Medication access difficulties and flares were common among rheumatology patients from the Bronx, New York in the month following the peak of the epidemic. Medication access difficulty and COVID-19-related distress were highly associated with flare and disease activity. COVID-19-related distress was associated with overall health scores.

Rapid Implementation of a Multidisciplinary COVID-19 Cytokine Storm Syndrome Task Force.

OBJECTIVE: Patients with coronavirus disease 2019 (COVID-19) can progress to a state of unregulated inflammation called cytokine storm syndrome (CSS). We describe formation and operation of a COVID-19 multidisciplinary consultation service that was allowed to individualize treatment for critically ill patients with COVID-19 during the pandemic. METHODS: Institutional experts from different subspecialties formed a COVID-19 CSS task force at Montefiore Medical Center, Bronx, NY. They agreed on a set of four clinical and six laboratory parameters that can help early identify COVID-19 CSS. We describe the formation and implementation of the COVID-19 task force. The case series description of the COVID-19 CSS consultation cohort highlights consultation volume, baseline characteristics, clinical and laboratory parameters, and how biologic treatments were allocated to these patients. RESULTS: Between April 4,2020, and May 7,2020, the COVID-19 CSS task force was formed, consisting of adult and pediatric rheumatologists and allergy and immunology physicians. The task force evaluated a total of 288 patients, of whom 197 (68%) were male, the median (interquartile range [IQR]) age was 62 (51-70) years, 122 (42%) were Hispanic, and 88 (31%) were Black or African American. The common presenting symptoms in all referred patients were dyspnea (85%) and diarrhea (80%). Thirty-one patients who received biologic therapy were younger, with a median (IQR) age of 53 (32-63) years, as opposed to 62.5 (52-70) years in the nonbiologic group (P = 0.008). A higher proportion receiving biologics was in the critical care setting (26 [84%] vs 151 [59%]; P = 0.006). CONCLUSION: To the best of our knowledge, this is the first multidisciplinary collaborative effort to provide individualized patient recommendations for evaluation and treatment of patients with COVID-19 who may have CSS. This working model helped to devise an approach that may have identified patients who were most likely to benefit from biologic therapy in the absence of evidence-based guidelines.

Outcomes of ST-elevation myocardial infarction by age and sex in a low-income urban community: The Montefiore STEMI Registry.

OBJECTIVES: To compare outcomes by age and sex in race/ethnic minorities presenting with ST-elevation myocardial infarction (STEMI), as studies are limited. METHODS: We studied sociodemographics, management, and outcomes in 1208 STEMI patients evaluated for primary percutaneous coronary intervention between 2008 and 2014 at Montefiore Health System (Bronx, NY). A majority of patients self-identified as nonwhite, and nearly two-thirds were young (<45 years) or middle-aged (45-64 years). RESULTS: Risk factors varied significantly across age groups; with more women and non-Hispanic whites, hypertension, diabetes, dyslipidemia, prior cardiovascular disease, non-sinus rhythm, and collagen vascular disease in the older age group (≥65 years); and higher body mass index, smoking, cocaine use, human immunodeficiency virus (HIV) infection and family history of heart disease in the young. Younger women had lower summary socioeconomic scores than younger men. Middle-aged women had more obesity and dysmetabolism, while men had more heavy alcohol use. There was greater disease severity with increasing age; with higher cardiac biomarkers, 3-vessel disease, cardiogenic shock, and coronary artery bypass grafting. Older patients had higher rates of death and death or readmission over 4.3 (interquartile range 2.4, 6.0) years of follow-up. Middle-aged women had higher rates of death or any readmission than men, but these differences were not significant after adjustment. CONCLUSIONS: These findings indicate a high burden of risk factors in younger adults with STEMI from an inner-city community. Programs to target sociobehavioral factors in disadvantaged settings, including substance abuse, obesity, and risk of HIV, are necessary to more effectively address health disparities in STEMI and its adverse consequences.

Methodological considerations in comparing access to Pre-emptive renal transplantation between SLE and other ESRD causes in the USRDS.

BACKGROUND: We compared pre-emptive transplant rates between SLE and non-SLE end-stage renal disease (ESRD) from the U.S. Renal Data System (USRDS) and investigated the potential influence of frequency matching and primary ESRD causes in the non-SLE group. METHODS: 4830 adult SLE patients with incident ESRD from USRDS 2005-2009 were frequency matched by age, sex and race to 4830 patients with incident non-SLE ESRD. Multivariable logistic regression models were used to estimate the odds of pre-emptive transplantation in SLE and non-SLE, and with the non-SLE subgroups by primary ESRD cause. RESULTS: The odds ratios (OR) of receiving a pre-emptive transplant were similar among non-SLE and SLE (referent group): OR = 1.18 (95% CI: 0.92, 1.50; p = 0.20). However, the ORs for receiving a pre-emptive transplant were 0.19 (95% CI: 0.08, 0.42) in type 2 diabetes ESRD, 0.42 (95% CI: 0.23, 0.75) for hypertension-associated ESRD, 1.67 (95% CI: 1.10, 2.54) in type 1 diabetes ESRD, and 2.06 (95% CI: 1.55, 2.73) for "other" ESRD. In contrast to non-SLE, younger SLE patients were less likely to receive a pre-emptive transplant than older SLE patients. CONCLUSION: The results of this study provide compelling evidence that major improvements need to be made in optimizing access to pre-emptive transplantation in SLE by addressing sociodemographic disparities and the unique challenges faced by SLE patients. Applying careful matching and selecting appropriate comparison groups in future studies may facilitate the development of effective strategies to address these barriers and to increase the number of pre-emptive renal transplants among SLE patients.

The complex associations between obstructive sleep apnea and auto-immune disorders: A review.

Obstructive sleep apnea is known to be associated with diseases such as hypertension, metabolic disorder, and cancer. A more controversial and less understood association is that of sleep apneas and the development and worsening of autoimmune and rheumatologic disorders. Through the main pathways of intermittent hypoxia and sleep deprivation, we hypothesize that obstructive sleep apnea creates a chronic inflammatory state that worsens or incites autoimmune disorders. This thorough review of the available literature highlights our current understanding of the relationship between these disease processes in order to demonstrate the importance of diagnosis and appropriate management of sleep disorders in patients suffering from rheumatologic diseases.

Sex Differences in Health Care Utilization, End-Stage Renal Disease, and Mortality Among Medicaid Beneficiaries With Incident Lupus Nephritis.

OBJECTIVE: While systemic lupus erythematosus and lupus nephritis (LN) disproportionately affect females, previous studies suggest that males may experience poorer outcomes. We undertook this study to investigate sex differences in health care utilization, end-stage renal disease (ESRD), and mortality among patients with LN receiving Medicaid, public insurance for low-income individuals. METHODS: Within the Medicaid Analytic eXtract (MAX) from 29 states (from 2000 to 2010), we used billing claims to identify individuals ages 5-65 years with incident LN (positive predictive value 80%). MAX data were linked to the US Renal Data System to determine ESRD and to Social Security Death Index files to determine death. We estimated adjusted incidence rate ratios (IRRs) by sex for health care utilization using Poisson regression, and we used multivariable proportional hazards models to compare risks of ESRD and death by sex. RESULTS: Of 2,750 patients with incident LN, 283 (10%) were male. The mean ± SD follow-up period for both sexes was 3.1 ± 2.3 years. The mean ± SD age was 29.6 ± 13.9 years among females and 24.7 ± 14.1 years among males (P < 0.01). Males had fewer outpatient visits (IRR 0.88 [95% confidence interval (95% CI) 0.80-0.97]) and fewer emergency department visits (IRR 0.75 [95% CI 0.63-0.90]). The 5-year cumulative incidence of ESRD was 22.3% in males and 21.2% in females. The 5-year cumulative incidence of death was 9.4% in males and 9.8% in females. Comparing males to females, there were no sex differences in ESRD (subdistribution hazard ratio [HR] 1.05 [95% CI 0.76-1.45]) or death (HR 0.81 [95% CI 0.47-1.35]). CONCLUSION: In this cohort of patients with incident LN, ESRD and mortality were extremely high overall but were not increased among males compared to females. In this vulnerable population, biologic and health care utilization differences by sex may not significantly affect outcomes.

Tubulointerstitial damage predicts end stage renal disease in lupus nephritis with preserved to moderately impaired renal function: A retrospective cohort study.

OBJECTIVES: The presence of tubulointerstitial damage (TID) on renal biopsy is considered to be a late sequela of lupus nephritis (LN). The objective of this study was to determine if TID predicts progression to end stage renal disease (ESRD) in LN patients without advanced kidney disease. METHODS: All SLE patients with an index biopsy consistent with LN between January 2005 and July 2015, and eGFR ≥ 30mL/min/1.73m2 were included. Moderate-to-severe TID was defined as the presence of moderate-to-severe tubular atrophy and/or interstitial fibrosis. Time to ESRD was defined as time from the index biopsy date to incident ESRD date; non-ESRD patients were censored at the time of death or the last visit before December 2015. Time-dependent analyses were conducted to evaluate whether moderate-to-severe TID was predictive of ESRD progression. RESULTS: Of the 131 LN patients with eGFR ≥ 30mL/min/1.73m2, 17 (13%) patients progressed to ESRD. Moderate-to-severe TID was present in 13% of biopsies with eGFR ≥ 60mL/min/1.73m2 and in 33% of biopsies with eGFR between 30 and 60mL/min/1.73m2. Moderate-to-severe TID was associated with a higher risk of ESRD progression: adjusted hazard ratio (HR) = 4.1, 95% CI: 1.4-12.1, p = 0.01 for eGFR ≥ 30mL/min/1.73m2; HR = 6.2, 95% CI: 1.7-23.2, p = 0.008 for eGFR ≥ 60mL/min/1.73m2. There was no association between tubulointerstitial inflammation (TII) and ESRD progression. CONCLUSIONS: Moderate-to-severe TID, but not TII, was a strong predictor of ESRD progression independent of eGFR or glomerular findings, therefore, providing an important window for potential early interventions.