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To determine if hydroxychloroquine (HCQ) dose is associated with adverse cardiac outcomes in patients with SLE.Patients with SLE on HCQ and with ≥1 echocardiogram followed at a tertiary care center in Bronx, NY between 2005-2021 were included. HCQ weight-based dose at 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 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 secondary analysis.Of 294 patients, 37 (13%) developed the outcome over a median (IQR) follow up time of 7.9 (4.2, 12.3) years. In non-smokers (n=226), multivariable analysis adjusted for age, body mass index, hypertension, chronic kidney disease, diabetes and thromboembolism showed that higher HCQ weight-based doses were not associated with an increased risk of the outcome, sHR 0.62 (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), sHR 0.85 (0.53, 1.34) per mg/kg, p=0.48. Propensity score analysis showed comparable results.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 non-smokers. This article is protected by copyright. All rights reserved.

BackgroundSLE 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.MethodsWe 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.ResultsFifty-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).ConclusionsLupus 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.

IntroductionTreatment 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.MethodsIn 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 (50%).ResultsRenal 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.ConclusionThis 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.

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/1.73m 2 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/1.73m 2 , 17 (13%) patients progressed to ESRD. Moderate-to-severe TID was present in 13% of biopsies with eGFR ≥ 60mL/min/1.73m 2 and in 33% of biopsies with eGFR between 30 and 60mL/min/1.73m 2 . 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/1.73m 2 ; HR=6.2, 95% CI: 1.7–23.2, p = 0.008 for eGFR ≥ 60mL/min/1.73m 2 . 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.

Background: Hydroxychloroquine (HCQ) use in SLE has been associated with a lower risk of end-organ damage, SLE flares, and thrombosis, with potential mortality benefit among SLE with end stage renal disease (ESRD)1, 2, 3. However, fewer than 30% of SLE continue HCQ after ESRD onset3. On the other hand, there is an increased risk of HCQ toxicity among SLE-ESRD4. It has not been studied what factors are associated with HCQ use after ESRD. Understanding these factors may inform future studies assessing the safety and efficacy of HCQ in SLE-ESRD and address the “confounding by-indication” bias (i.e. different treatments are intentionally chosen for patients with different prognoses) when analyzing retrospective data regarding HCQ use in SLE patients with ESRD. Objectives: To determine the factors associated with HCQ use among SLE patients with ESRD. Methods: We performed a retrospective chart review of SLE patients with ESRD at a single tertiary care center between 2010-2017. All included patients met ACR and/or SLICC criteria for SLE and had at least one visit with rheumatology, nephrology, or primary care, before and after the development of ESRD. SLE-related symptoms, serologic markers of disease activity, and rheumatology visits were identified, both pre- and post-ESRD onset. Transplanted patients were excluded at the time of their first renal transplant. Results: A total of 69 patients were included, 58 had pre-ESRD data. Of these patients, 33/58 (57%) were taking HCQ prior to ESRD onset. Following the diagnosis of ESRD, 40/69 (58%) were prescribed HCQ within six months after ESRD onset. Of these, six discontinued HCQ by the last documented visit, and one patient initiated HCQ six months after ESRD onset (prescribed by a rheumatologist). At the last documented visit, 35/69 patients (51%) had an active HCQ prescription. Patients taking HCQ were younger, more likely to be followed by a rheumatologist, had a higher frequency of documented arthritis, higher frequency of corticosteroid use and immunosuppressive medication use (Table 1). A history of oral ulcers, cytopenias, and elevated levels of dsDNA at any point (either pre or post-ESRD onset) was not significantly associated with HCQ use at the last visit. Conclusion: HCQ is more likely to be continued among patients with signs of persistently active SLE. HCQ was more likely to be prescribed by a rheumatologist and was associated with the presence of arthritis. Limited systemic evaluation and documentation by the different providers may have resulted in under-reporting of some of the SLE symptoms. However, these findings reflect the “real-world” experience with HCQ use after ESRD in a large tertiary care center. References [1] Jung H, et al. Arthritis and rheumatism. 2010;62(3):863-8. [2] Ruiz-Irastorza G, et al. Annals of the rheumatic diseases. 2010;69(1):20-8. [3] Broder A, et al. The Journal of rheumatology. 2011;38(11):2382-9. [4] Bertsias GK, et al. Annals of the rheumatic diseases. 2012;71(11):1771-82. Disclosure of Interests: None declared

Background: SLE disease activity tends to diminish after the development of end stage renal disease (ESRD)1, 2. Nonetheless, some patients continue to show signs of active disease and experience flares after ESRD3. To date, little is known about the evolution of SLE-related symptoms pre and post ESRD. Whether specific symptoms abate after ESRD or a shift towards different manifestations occurs deserves further study. Prompt identification of subtler SLE manifestations is further complicated by a trend towards poor rheumatology follow once ESRD develops. SLE manifestations post-ESRD may be underdiagnosed and undertreated contributing to increased morbidity and mortality. Objectives: To study the different clinical manifestations and serological markers of SLE disease activity before and after ESRD development. Methods: We performed a retrospective chart review of SLE patients with ESRD at a tertiary care center between the years of 2010 and 2017. SLE was defined by ACR and/or SLICC criteria. SLE ESRD patients were included if they had at least one visit with rheumatology, nephrology, or primary care pre- and post-ESRD. SLE-related symptoms and serologic markers of disease activity were identified from chart review before and after ESRD onset. Results: Fifty-eight patients were included. Twenty-five patients had a least one clinical non-renal criteria documented pre-ESRD. Of them, 14 achieved complete clinical remission post-ESRD. Post-ESRD, cytopenias persisted in 49 of the 55 patients who were cytopenic pre-ESRD. Arthritis persisted in 3 of the 13 patients who had arthritis pre-ESRD. Of the 37 patients with hypocomplementemia pre-ESRD, 29 remained hypocomplementemic post-ESRD. Twenty-nine had elevated dsDNA pre-ESRD, of them, dsDNA remained elevated in 16 patients post-ESRD. Six patients developed at least one new clinical criteria post-ESRD. Three patients developed low complement, 5 developed elevated dsDNA, 3 developed new onset of serositis and 4 new osent of arthritis post-ESRD. Conclusion: Lupus activity may diminish after ESRD onset. However, many patients experience persistent disease activity. New arthritis, serositis, low complements and elevated dsDNA may develop after ESRD. Limited evaluation and documentation of disease activity by non-rheumatology providers may have resulted in under-reporting of SLE signs and symptoms on this study. SLE ESRD patients should be carefully evaluated for subtle signs of active SLE. References: [1] Mattos P, Santiago MB. Clin Rheumatol. 2012; 31:897–905. [2] Stone JH. Lupus. 1998; 7:654–659. [3] Krane NK, Burjak K, Archie M, O’Donovan R. Am J Kidney Dis. 1999; 33:872–879. Disclosure of Interests: None declared

Background:Hydroxychloroquine (HCQ) cardiotoxicity remains an underrecognized condition. Diagnosis ultimately relies on invasive endomyocardial biopsy (EMB) and non-invasive screening methods are warranted. Strain imaging is a novel tool to detect early subclinical left ventricular (LV) dysfunction and may have a role in screening for HCQ cardiotoxicity (1). Strain measures systolic deformation indices that when decreased can predict cardiovascular outcomes more accurately than LV ejection fraction (2).Objectives:We assessed whether high HCQ cardiotoxicity risk is associated with a specific strain pattern in a group of patients with SLE and end-stage renal disease (ESRD).Methods:This was a retrospective study in a tertiary care center in New York on a group of patients with an established diagnosis of SLE, ESRD and cardiomyopathy on the index echocardiogram followed between years 2003 and 2019. The patients were stratified into two groups: high risk HCQ toxicity group was defined as either cumulative HCQ dose ≥1000g and/or an endomyocardial biopsy confirming HCQ toxicity. Low/moderate risk group was defined as a cumulative dose of HCQ Results:A total of 16 patients were included. Two patients had EMB consistent with HCQ induced toxicity and 3 patients had cumulative HCQ doses ≥1000g. There were no significant differences in the baseline demographic characteristics between the two groups. Compared to patients with low/moderate risk, patients in the high risk group had a lower heart rate at the time of the echocardiogram (69 vs 87 beats per minute, p=0.08) and a higher frequency of LV hypertrophy (40% vs 9.1%, p=0.2). Strain analysis showed that both groups had compromised LV global longitudinal strain (GLS) and global cross-sectional strain (GCS). However, compared to the low/moderate risk group, the high risk group had a weaker LV GLS (-12.3% vs -14.9%, p=0.27).Characteristics overall and stratified by HCQ risk groupCharacteristicOverall (n=16)Low/Moderate HCQ Risk(n=11)High HCQ Risk and/or Positive EMB (n=5)P valueDemographicsAge, years47.5 (36.5,60.7)50.0 (33.9,60.5)42.5 (42.7,61.0)0.95Female, n(%)14 (87.5)9 (90)5 (83.3)0.99Clinical FeaturesSLE duration, years7.4 (4.3,17.5)5.5 (3.5,13.2)15.6 (11.6,19.3)0.15HCQ cumulative dose, g422.8 (224.2,422.8)285.4 (110.8,523.6)1140 (1006,1625.4)0.005HCQ therapy duration, years3.4 (2.5, 8.9)3.2 (1.5,5.1)7.8 (6.8,11.6)0.06HCQ daily dose, mg/d226 (200,394.9)200 (179.4,253.7)400 (389.8,400)0.007Hypertension, n (%)14 (87.5)10 (90.9)4 (80.0)0.99Diabetes, n (%)3 (18.8)2 (18.8)1 (20.0)0.99CAD, n (%)3 (18.8)2 (18.8)1 (20)0.99EchocardiogramEF, %55 (42.5,60)55 (40,60)55 (55,70)0.45LA size, cm3.8 (3.4,4.3)3.8 (3.4,4.2)4.3 (3.4,4.9)0.30LVEDD, cm4.9 (4.4, 5.5)4.8 (4.2,5.5)5.0 (4.9,5.4)0.43E/E’12.3 (8.8,16.3)12 (8.8,14.9)16.9 (4.9,21.8)0.43Moderate-severe LV hypertrophy, n(%)3 (18.7)1 (9.1)2 (40.0)0.20Strain echocardiographyGLS, %-13.9 (-16.7,-12.3)-14.9 (-16.7,-12.9)-12.3 (-15.4,-12.2)0.27Base/Apex Ratio0.8 (0.7,0.9)0.76 (0.68,0.86)0.76 (0.66,0.83)0.95GCS, %-20.2 (-21.7,-17)-19.7 (-20.5,18.0)-21.7 (-23.9,-20.9)0.16RV GLS, %-20.19 (-22.1,-17.5)-20.2 (-22.3,-17.1)-19.8 (-22.1,-17.5)0.99Conclusion:We report an association of higher HCQ cardiotoxicity risk and impaired strain in a set of SLE ESRD patients. Standard echo measures did not differentiate between high and low/moderate risk patients. Although the findings did not reach statistical significance, given the small sample size, results are still suggestive of a possible utility of strain echocardiography for detection of early HCQ toxicity.References:[1]Buss SJ, et al. J Rheumatol. 2010;37(1):79-86[2]Kalam K, et al. Heart. 2014;100(21):1673-80Disclosure of Interests: None declared

Background Moderate-to-severe tubulointerstitial damage (TID) is associated with poor renal outcomes in lupus nephritis (LN) independent of glomerular pathology 1 . Specific antibody profiles associated with TID in LN have not been identified. Unlike glomerular damage, TID is not associated with anti-dsDNA or complement levels 1 . An association between TID and the presence of anti-Ro/La antibodies has been proposed in Sjogren9s syndrome 2 . Whether these antibodies are associated with TID in LN is not known. Objectives To study an association between anti-Ro/La antibodies and moderate-to-severe TID in LN. Methods We identified all patients who fulfilled ACR and/or SLICC criteria for SLE. Patients were included if they had an index renal biopsy consistent with LN between January 2005 and July 2015 and had complete data on TID and anti-Ro/La. Medical history, demographic and laboratory data were ascertained from chart review. TID was defined as the presence of moderate or severe tubular atrophy and/or interstitial fibrosis from the renal biopsy reports. Results of the 157 LN patients, 39 (25%) had moderate/severe TID (Table). As expected, moderate/severe TID was associated with older age, class III/IV±V LN and lower estimated glomerular filtration rate (eGFR) at biopsy. Anti-Ro antibodies were present in 55 (47%) of patients with none/mild TID and 17 (44%) of patients with moderate/severe TID (p=0.74). Both anti-Ro and anti-La antibodies were present in 11 (9%) of patients with none/mild TID vs 11 (28%) of patients with moderate/severe TID (p=0.003). In the logistic regression model adjusted for age, eGFR and LN class, the presence of both anti-Ro and anti-La antibodies was associated with a 3-fold increase in the odds of TID, OR 3.1, 95% CI (1.1–9.1), p=0.04. Conclusions The presence of anti-Ro and anti-La antibodies is associated with moderate/severe TID, independent of age, LN class and eGFR. Understanding the role of anti-Ro/La in the mechanisms underlying TID in LN may lead to novel preventive and therapeutic strategies. References Yu F, et al. Kidney Int 2010;77:820–9. Francois H, et al. Nat Rev Nephrol, 2016;12(2):82–93. Disclosure of Interest None declared