Predictive factors for lupus nephritis and its long-term outcomes

Abstract

Predictive factors for lupus nephritis and its long-term outcomes

Background and Objectives Systemic Lupus Erythematosus (SLE) is an autoimmune disease with unpredictable progression and complex etiology, affecting various organs from skin manifestations to neurologic involvement (1). Lupus Nephritis (LN), a complication of SLE, is associated with decreased survival in SLE patients and could progress to End Stage Renal Disease (ESRD), emphasizing its clinical significance (2). Despite advances in understanding the pathophysiology of LN and overall medical treatment, LN patients still experience high mortality rates, ESRD incidence, and diminished quality of life (3, 4). Therefore, a detailed understanding of risk factors for LN occurrence and predictors of negative long-term outcomes such as ESRD and death is crucial for developing accurate biomarkers and assessing SLE patients. The first objective of this study was to investigate the associated factors for the presence of LN in patients with SLE, while the secondary objective was to investigate risk factors for ESRD and mortality in patients with LN.

Methods 1. Clinical and genetic risk factors associated with the presence of lupus nephritis using mediation analysis A total of 1,078 SLE patients registered in the BAE Lupus Cohort from January 1998 to December 2018 were divided into LN group (n=507) and non-LN (n=571) group. The study examined demographic and clinical information at enrollment, as well as SLE Disease Activity Index-2000 (SLEDAI-2K) (5) and Systemic Lupus International Collaborating Clinics Damage Index scores (SDI) (6) assessed annually. The study investigated whether the weighted Genetic Risk Scores (wGRS) (7) and clinical characteristics were associated with the presence of LN. The wGRS, calculated based on 113 single nucleotide polymorphisms (SNPs) representing 112 non-HLA regions (8), and amino acid positions 11, 13, and 26 of the HLA-DRβ1 gene (9), was derived from genome-wide association studies (GWAS) on lupus susceptibility (10). 2. Predictors of long-term renal survival and mortality in patients with biopsy-proven Class III, IV/±V lupus nephritis A total of 599 patients with biopsy-proven Class III, IV/±V patients with LN registered in the BAE Lupus Cohort from January 1998 to December 2018 were evaluated. The patient information and clinical data, as collected in previous study, were also assessed. The development of ESRD and mortality in these patients were assessed, and risk factors were analyzed.

Results 1. In the multivariate analysis, age at diagnosis (odds ratio [OR]=0.97, p＜0.001), pleuritis (OR=2.44, p＜0.001), pericarditis (OR=1.62, p=0.029), anti-double stranded deoxyribonucleic acid (anti-dsDNA antibodies, OR=2.22, p＜0.001), anti-Smith antibodies (anti-Sm antibodies, OR=1.70, p=0.002), low level of complement (OR=1.37, p=0.043), anti-phospholipid antibodies (aPL antibodies, OR=0.63, p=0.002), and wGRS (OR=1.16, p=0.012) were associated with the presence of LN. 2. Among 599 patients with proliferative (Class III and IV/±V) and membranous (Class V) LN, 42 (7.0%) progressed to ESRD. High aPL antibody levels (OR=2.9, p=0.032) and a high activity index score in renal biopsy (OR=1.1, p=0.048) were identified as independent predictors of ESRD. Of the 31 deceased patients, those who did not progress to ESRD showed superior overall survival (p=0.028). Higher adjusted mean SLEDAI-2K scores (OR=1.43, p<0.001) and extra-renal AMS (adjusted mean SLEDAI-2K excluding renal items, OR=1.83, p<0.001) were associated with a significantly increased overall mortality rate.

Conclusion This study investigated associations between younger age at onset, pleuritis, pericarditis, several serological markers, and a higher wGRS with LN occurrence. It also identified anti-Sm antibodies and low complement levels as indirect mediators between wGRS and LN occurrence. Furthermore, the study revealed key predictors of poor long-term outcomes, namely ESRD and mortality, in LN patients.

Reference

1. Hoover PJ, Costenbader KH. Insights into the epidemiology and management of lupus nephritis from the US rheumatologist's perspective. Kidney Int. 2016;90(3):487-92. 2. Reppe Moe SE, Molberg Ø, Strøm EH, Lerang K. Assessing the relative impact of lupus nephritis on mortality in a population-based systemic lupus erythematosus cohort. Lupus. 2019;28(7):818-25. 3. Hanly JG, O'Keeffe AG, Su L, Urowitz MB, Romero-Diaz J, Gordon C, et al. The frequency and outcome of lupus nephritis: results from an international inception cohort study. Rheumatology (Oxford). 2016;55(2):252-62. 4. Kono M, Yasuda S, Kato M, Kanetsuka Y, Kurita T, Fujieda Y, et al. Long-term outcome in Japanese patients with lupus nephritis. Lupus. 2014;23(11):1124-32. 5. Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002;29(2):288-91. 6. Gladman D, Ginzler E, Goldsmith C, Fortin P, Liang M, Urowitz M, et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum. 1996;39(3):363-9. 7. Igo RP, Jr., Kinzy TG, Cooke Bailey JN. Genetic Risk Scores. Curr Protoc Hum Genet. 2019;104(1):e95. 8. Yin X, Kim K, Suetsugu H, Bang SY, Wen L, Koido M, et al. Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus. Ann Rheum Dis. 2021;80(5):632-40. 9. Kim K, Bang SY, Lee HS, Okada Y, Han B, Saw WY, et al. The HLA-DRβ1 amino acid positions 11-13-26 explain the majority of SLE-MHC associations. Nat Commun. 2014;5:5902. 10. Dudbridge F. Power and predictive accuracy of polygenic risk scores. PLoS Genet. 2013;9(3):e1003348.