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Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis
Horisberger, Alice; Griffith, Alec; Keegan, Joshua; Arazi, Arnon; Pulford, John; Murzin, Ekaterina; Howard, Kaitlyn; Hancock, Brandon; Fava, Andrea; Sasaki, Takanori; Ghosh, Tusharkanti; Inamo, Jun; Beuschel, Rebecca; Cao, Ye; Preisinger, Katie; Gutierrez-Arcelus, Maria; Eisenhaure, Thomas M; Guthridge, Joel; Hoover, Paul J; Dall'Era, Maria; Wofsy, David; Kamen, Diane L; Kalunian, Kenneth C; Furie, Richard; Belmont, Michael; Izmirly, Peter; Clancy, Robert; Hildeman, David; Woodle, E Steve; Apruzzese, William; McMahon, Maureen A; Grossman, Jennifer; Barnas, Jennifer L; Payan-Schober, Fernanda; Ishimori, Mariko; Weisman, Michael; Kretzler, Matthias; Berthier, Celine C; Hodgin, Jeffrey B; Demeke, Dawit S; Putterman, Chaim; Brenner, Michael B; Anolik, Jennifer H; Raychaudhuri, Soumya; Hacohen, Nir; James, Judith A; Davidson, Anne; Petri, Michelle A; Buyon, Jill P; Diamond, Betty; Zhang, Fan; Lederer, James A; Rao, Deepak A
Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying non-invasive, blood-based immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation and identify correlates of renal parameters. Unbiased analysis identified three immunologically distinct groups of patients that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at one year. Patients with enriched circulating granzyme B+ T cells showed more active disease and increased numbers of activated CD8 T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive but with chronic renal injuries. The major immunologic axes of variation could be distilled down to five simple cytometric parameters that recapitulate several clinical associations, highlighting the potential for blood immunoprofiling to translate to clinically useful non-invasive metrics to assess immune-mediated disease in LN.
PMID: 40536813
ISSN: 1558-8238
CID: 5871202
2024 American College of Rheumatology (ACR) Guideline for the Screening, Treatment, and Management of Lupus Nephritis
Sammaritano, Lisa R; Askanase, Anca; Bermas, Bonnie L; Dall'Era, Maria; Duarte-García, Alí; Hiraki, Linda T; Rovin, Brad H; Son, Mary Beth F; Alvarado, Anthony; Aranow, Cynthia; Barnado, April; Broder, Anna; Brunner, Hermine I; Chowdhary, Vaidehi; Contreras, Gabriel; Felix, Christele; Ferucci, Elizabeth D; Gibson, Keisha L; Hersh, Aimee O; Izmirly, Peter M; Kalunian, Kenneth; Kamen, Diane; Rollins, Brandi; Smith, Benjamin J; Thomas, Asha; Timlin, Homa; Wallace, Daniel J; Ward, Michael; Azzam, Muayad; Bartels, Christie M; Cunha, Joanne S; DeQuattro, Kimberly; Fava, Andrea; Figueroa-Parra, Gabriel; Garg, Shivani; Greco, Jessica; Cuéllar-Gutiérrez, Maria C; Iyer, Priyanka; Johannemann, Andrew S; Jorge, April; Kasturi, Shanthini; Kawtharany, Hassan; Khawandi, Jana; Kirou, Kyriakos A; Legge, Alexandra; Liang, Kelly V; Lockwood, Megan M; Sanchez-Rodriguez, Alain; Turgunbaev, Marat; Williams, Jessica N; Turner, Amy S; Mustafa, Reem A
OBJECTIVE:The objective is to provide evidence-based and expert guidance for the screening, treatment, and management of lupus nephritis. METHODS:The Core Team developed clinical questions for screening, treatment, and management of lupus nephritis using the PICO format (population, intervention, comparator, and outcome). Systematic literature reviews were completed for each PICO question, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the quality of evidence and to formulate recommendations. The Voting Panel achieved a consensus ≥70% on the direction (for or against) and strength (strong or conditional) of each recommendation. RESULTS:We present 28 graded recommendations (7 strong, 21 conditional) and 13 ungraded, consensus-based good practice statements for the screening and management of lupus nephritis. Our recommendations focus on the unifying principle that lupus nephritis therapy is continuous and ongoing, rather than consisting of discrete induction/initial and maintenance/subsequent therapies. Therapy should include pulse glucocorticoids followed by oral glucocorticoid taper and two additional immunosuppressive agents for 3-5 years for those achieving complete renal response. CONCLUSION/CONCLUSIONS:This guideline provides direction for clinicians regarding screening and treatment decisions for management of lupus nephritis. These recommendations should not be used to limit or deny access to therapies, as treatment decisions may vary due to the unique clinical situation and personal preferences of each individual patient.
PMID: 40331662
ISSN: 2326-5205
CID: 5839162
Adverse Pregnancy Outcomes in Sjogren's Disease Compared to Controls: An Interdisciplinary Approach with Maternal-Fetal Medicine
Tesoriero, Lauren; Kidd, Jennifer; Piccione, Julie; Izmirly, Peter; Akerman, Meredith; Carsons, Steven; Rekawek, Patricia; Nusbaum, Julie
OBJECTIVES/UNASSIGNED:Outside of the association of SS-A antibody with congenital heart block, little is known about adverse maternal and neonatal outcomes, in patients with Sjogren's disease (SjD). Our study involved collaboration with maternal-fetal medicine (MFM). METHODS/UNASSIGNED:-test and Fisher's exact test. RESULTS/UNASSIGNED:48 patients were included: 12 SjD patients and 36 controls. APO was significantly increased in SjD with one preterm birth, one fetal growth restriction, and one limb anomaly; non-SjD had one cardiac anomaly. There were no cases of CHB. SjD patients were more likely to be delivered by cesarean delivery. CONCLUSION/UNASSIGNED:There was an increased risk of APO in SjD patients compared with controls. No significant difference in neonatal outcomes was found. We speculate that placental pathology may play a role in pathophysiology and future studies should be performed. KEY POINTS/UNASSIGNED:There was an increased risk of APO in SjD patients compared with controls.No significant difference in neonatal outcomes was found.We speculate that placental pathology may play a role in pathophysiology, prompting future studies.
PMCID:12020534
PMID: 40291586
ISSN: 2157-6998
CID: 5833052
2024 American College of Rheumatology (ACR) Guideline for the Screening, Treatment, and Management of Lupus Nephritis
Sammaritano, Lisa R; Askanase, Anca; Bermas, Bonnie L; Dall'Era, Maria; Duarte-García, Alí; Hiraki, Linda T; Rovin, Brad; Son, Mary Beth F; Alvarado, Anthony; Aranow, Cynthia; Barnado, April; Broder, Anna; Brunner, Hermine I; Chowdhary, Vaidehi; Contreras, Gabriel; Felix, Christele; Ferucci, Elizabeth D; Gibson, Keisha L; Hersh, Aimee O; Izmirly, Peter M; Kalunian, Kenneth; Kamen, Diane; Rollins, Brandi; Smith, Benjamin J; Thomas, Asha; Timlin, Homa; Wallace, Daniel J; Ward, Michael; Azzam, Muayad; Bartels, Christie M; Cunha, Joanne S; DeQuattro, Kimberly; Fava, Andrea; Figueroa-Parra, Gabriel; Garg, Shivani; Greco, Jessica; Cuéllar-Gutiérrez, Maria C; Iyer, Priyanka; Johannemann, Andrew S; Jorge, April; Kasturi, Shanthini; Kawtharany, Hassan; Khawandi, Jana; Kirou, Kyriakos A; Legge, Alexandra; Liang, Kelly V; Lockwood, Megan M; Sanchez-Rodriguez, Alain; Turgunbaev, Marat; Williams, Jessica N; Turner, Amy S; Mustafa, Reem A
The accepted version of this article was posted prematurely on March 24, 2025. The final version of record will be made fully available at a later date.
PMID: 40127995
ISSN: 2151-4658
CID: 5814862
Extrarenal symptoms associate with worse quality of life in patients enrolled in the AMP RA/SLE Lupus Nephritis Network
Carlucci, Philip M; Preisinger, Katherine; Deonaraine, Kristina K; Zaminski, Devyn; Dall'Era, Maria; Gold, Heather T; Kalunian, Kenneth; Fava, Andrea; Belmont, H Michael; Wu, Ming; Putterman, Chaim; Anolik, Jennifer; Barnas, Jennifer L; Furie, Richard; Diamond, Betty; Davidson, Anne; Wofsy, David; Kamen, Diane; James, Judith A; Guthridge, Joel M; Apruzzese, William; Rao, Deepak; Weisman, Michael H; ,; Izmirly, Peter M; Buyon, Jill; Petri, Michelle
OBJECTIVE:Lupus nephritis (LN) can occur as an isolated component of disease activity or be accompanied by diverse extrarenal manifestations. Whether isolated renal disease is sufficient to decrease health related quality of life (HRQOL) remains unknown. This study compared Patient-Reported Outcomes Measurement Information System 29-Item (PROMIS-29) scores in LN patients with isolated renal disease to those with extrarenal symptoms to evaluate the burden of LN on HRQOL and inform future LN clinical trials incorporating HRQOL outcomes. METHODS:A total of 181 LN patients consecutively enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership completed PROMIS-29 questionnaires at the time of a clinically indicated renal biopsy. Raw PROMIS-29 scores were converted to standardized T scores. RESULTS:Seventy-five (41%) patients had extrarenal disease (mean age 34, 85% female) and 106 (59%) had isolated renal (mean age 36, 82% female). Rash (45%), arthritis (40%) and alopecia (40%) were the most common extrarenal manifestations. Compared with isolated renal, patients with extrarenal disease reported significantly worse pain interference, ability to participate in social roles, physical function, and fatigue. Patients with extrarenal disease had PROMIS-29 scores that significantly differed from the general population by > 0.5 SD of the reference mean in pain interference, physical function, and fatigue. Arthritis was most strongly associated with worse scores in these three domains. CONCLUSION/CONCLUSIONS:Most patients had isolated renal disease and extrarenal manifestations associated with worse HRQOL. These data highlight the importance of comprehensive disease management strategies that address both renal and extrarenal manifestations to improve overall patient outcomes.
PMID: 38530774
ISSN: 1462-0332
CID: 5644732
Low versus high initial oral glucocorticoid dose for lupus nephritis: a pooled analysis of randomised controlled clinical trials
Saxena, Amit; Sorrento, Cristina; Izmirly, Peter; Sullivan, Janine; Gamez-Perez, Monica; Law, Jammie; Belmont, Howard Michael; Buyon, Jill P
OBJECTIVE:Traditional initial treatment regimens for lupus nephritis (LN) used oral glucocorticoids (GC) in starting doses up to 1.0 mg/kg/day prednisone equivalent with or without a preceding intravenous methylprednisolone pulse. More recent management guidelines recommend lower starting oral GC doses following intravenous pulse therapy. As there have been no large studies directly comparing patients receiving low versus high initial oral GC doses, this pooled analysis of high-quality randomised controlled trials (RCTs) aims to evaluate differences in efficacy and safety. METHODS:Published data were analysed from RCTs that assessed variable GC doses in the standard of care (SOC) treatment arms. Patients receiving starting prednisone doses up to 0.5 mg/kg/day (low dose) were compared with 1.0 mg/kg/day (high dose). Complete renal response requiring urine protein-creatinine ratio <0.5 mg/mg (CRR 0.5), CRR or partial renal response (PRR), serious adverse events (SAE) and SAE due to infections at 12 months of treatment were compared between groups. RESULTS:417 patients from SOC arms of five studies were exposed to low-dose initial GC after intravenous pulse, while 521 patients from four studies were treated with high-dose oral GC. In patients with low-dose oral GC, 25.2% achieved CRR 0.5 at 12 months compared with 27.2% in high-dose groups, p=0.54. CRR or PRR was attained in 48.7% low-dose vs 43.6% high-dose patients, p=0.14. SAEs and infection SAEs were less common in the low-dose GC group (19.4% vs 31.6%, p<0.001 and 9.8% vs 16.5%, p=0.012, respectively). CONCLUSIONS:Based on pooled RCT data, there was no significant difference in 12-month renal responses between patients receiving low-dose prednisone following intravenous GC compared with those receiving initial high doses. SAEs were less frequent in patients receiving low-dose initial GC. These findings support the use of lower oral GC doses in LN treatment.
PMCID:11752037
PMID: 39762088
ISSN: 2053-8790
CID: 5778302
Substantiation of trophoblast transport of maternal anti-SSA/Ro autoantibodies in fetuses with rapidly progressive cardiac injury: implications for neonatal Fc receptor blockade
Buyon, Jill P; Carlucci, Philip M; Cuneo, Bettina F; Masson, Mala; Izmirly, Peter; Sachan, Nalani; Brandt, Justin S; Mehta-Lee, Shilpi; Halushka, Marc; Thomas, Kristen; Fox, Melanie; Phoon, Colin Kl; Ludomirsky, Achiau; Srinivasan, Ranjini; Lam, Garrett; Wainwright, Benjamin J; Fraser, Nicola; Clancy, Robert
PMID: 39557050
ISSN: 2665-9913
CID: 5758192
Evaluation and randomised controlled trial of home urinalysis testing in patients with SLE at elevated risk for developing lupus nephritis: a study protocol
Gold, Heather T; El Shahawy, Omar; Izmirly, Peter M; Masson, Mala; Cohen, Brooke; Buyon, Jill P
INTRODUCTION/BACKGROUND:Lupus nephritis (LN) is a frequent complication of SLE, occurring in up to 60% of adult patients and ultimately progressing from acute inflammation to chronicity with fibrosis and end-stage kidney failure in 10%-30% of patients. Racial/ethnic minority patients with lupus have worse long-term outcomes, including progression to end-stage renal disease and overall mortality. A major challenge in the management of patients with SLE is delayed identification of early kidney disease, which ultimately leads to a greater burden on both patients and the health system. METHODS AND ANALYSIS/METHODS:Using a mixed methods approach, this study will develop, adapt and evaluate a home urine sampling protocol with a text-messaging reminder and data capture system for patients at elevated risk of de novo LN or relapse. First, a feasibility pilot using a single-group trial design (n=18) will be implemented, with a feasibility assessment and qualitative, debriefing interviews with patients to further refine the intervention. The second phase is a comparative effectiveness trial of the intervention (n=160) with the primary outcome of biopsy eligibility, that is, the participant has a clinical indication for a kidney biopsy (urine protein-creatinine ratio≥0.5), whether or not the patient actually undergoes the biopsy procedure. The randomised trial includes an economic evaluation of the adapted home urinalysis protocol. DISCUSSION AND DISSEMINATION/CONCLUSIONS:It is unknown whether weekly home-based urine sampling can identify proteinuria sooner than standard care; if found sooner, kidney problems could be diagnosed earlier, hopefully leading to earlier care for less-involved disease and subsequent reduced morbidity. The data collected in this trial will inform future feasibility and effectiveness of text-messaging-based home urine sampling interventions. TRIAL REGISTRATION NUMBER/BACKGROUND:The randomised trial will be registered with ClincialTrials.gov prior to enrolment start.
PMCID:11590779
PMID: 39578016
ISSN: 2053-8790
CID: 5758982
Association of Autoantibody Concentrations and Trajectories With Lupus Nephritis Histologic Features and Treatment Response
Fava, Andrea; Wagner, Catriona A; Guthridge, Carla J; Kheir, Joseph; Macwana, Susan; DeJager, Wade; Gross, Tim; Izmirly, Peter; Belmont, H Michael; Diamond, Betty; Davidson, Anne; Utz, Paul J; Weisman, Michael H; Magder, Laurence S; ,; Guthridge, Joel M; Petri, Michelle; Buyon, Jill; James, Judith A
OBJECTIVE:Autoantibodies are a hallmark of lupus nephritis (LN), but their association with LN classes and treatment response are not adequately known. In this study, we quantified circulating autoantibodies in the Accelerating Medicines Partnership LN longitudinal cohort to identify serological biomarkers of LN histologic classification and treatment response and how these biomarkers change over time based on treatment response. METHODS:Peripheral blood samples were collected from 279 patients with systemic lupus erythematosus undergoing diagnostic kidney biopsy based on proteinuria. Of these, 268 were diagnosed with LN. Thirteen autoantibody specificities were measured by bead-based assays (Bio-Rad Bioplex 2200) and anti-C1q by enzyme-linked immunosorbent assay at the time of biopsy (baseline) and at 3, 6, and 12 months after biopsy. Clinical response was determined at 12 months. RESULTS:Proliferative LN (International Society of Nephrology/Renal Pathology Society class III/IV±V, n = 160) was associated with higher concentrations of anti-C1q, anti-chromatin, anti-double-stranded DNA (dsDNA), and anti-ribosomal P autoantibodies compared to nonproliferative LN (classes I/II/V/VI, n = 108). Anti-C1q and-dsDNA were independently associated with proliferative LN. In proliferative LN, higher baseline anti-C1q levels predicted complete response (area under the curve [AUC] 0.72; P = 0.002) better than baseline proteinuria (AUC 0.59; P = 0.21). Furthermore, all autoantibody levels except for anti-La/SSB decreased over 12 months in patients with proliferative, but not membranous, LN with a complete response. CONCLUSION/CONCLUSIONS:Baseline levels of anti-C1q and anti-dsDNA may serve as noninvasive biomarkers of proliferative LN, and anti-C1q may predict complete response at the time of kidney biopsy. In addition, tracking autoantibodies over time may provide further insights into treatment response and pathogenic mechanisms in patients with proliferative LN.
PMID: 38962936
ISSN: 2326-5205
CID: 5695772
Validating claims-based algorithms for a systemic lupus erythematosus diagnosis in Medicare data for informed use of the Lupus Index: a tool for geospatial research
Feldman, Candace; Curtis, Jeffrey R; Oates, Jim C; Yazdany, Jinoos; Izmirly, Peter
OBJECTIVE:This study aimed to validate claims-based algorithms for identifying SLE and lupus nephritis (LN) in Medicare data, enhancing the use of the Lupus Index for geospatial research on SLE prevalence and outcomes. METHODS:We retrospectively evaluated the performance of rule-based algorithms using the International Classification of Diseases, 10th Revision (ICD-10) codes to identify SLE and LN in a well-defined prospective longitudinal cohort of patients with and without SLE from a South Carolina registry and rheumatology outpatient clinics. The analysis included comparison of algorithms based on Medicare fee-for-service claims data to these rigorously phenotyped populations. The primary classification for SLE cases was based on the American College of Rheumatology and Systemic Lupus Erythematosus International Collaborating Clinics criteria for SLE and LN. Algorithms were based on the number of ICD-10 codes with and without a 30-day separation in the observation period, including all of 2016-2018. RESULTS:The algorithm using two ICD-10 codes for SLE, with or without a 30-day separation, showed the best overall performance. For LN, specific ICD-10 codes outperformed combinations of SLE and renal/proteinuria codes that were found in ICD-9. CONCLUSIONS:The findings of this study highlight the performance of specific ICD-10 code algorithms in identifying SLE and LN cases within Medicare data, providing a valuable tool for informing use of the Lupus Index. This index allows for improved geographical targeting of clinical resources, health disparity studies and clinical trial site selection. The study underscores the importance of algorithm selection based on research objectives, recommending more specific algorithms for precise tasks like clinical trial site identification and less specific ones for broader applications such as health disparities research.
PMCID:11474710
PMID: 39401954
ISSN: 2053-8790
CID: 5711592