Extrarenal symptoms associate with worse quality of life in patients enrolled in the AMP RA/SLE Lupus Nephritis Network.

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: 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.

Economic insecurities and patient-reported outcomes in patients with systemic lupus erythematosus in the USA: a cross-sectional analysis of data from the California Lupus Epidemiology Study.

BACKGROUND: Social determinants of health are consistently associated with systemic lupus erythematosus (SLE) outcomes. However, social determinants of health are typically measured with conventional socioeconomic status factors such as income or education. We assessed the association of economic insecurities (ie, food, housing, health care, and financial insecurity) with patient-reported outcomes in a cohort of patients with SLE. METHODS: In this cross-sectional analysis, data were derived from the California Lupus Epidemiology Study based in the San Francisco Bay Area, CA, USA. Participants were recruited between Feb 25, 2015, and Jan 10, 2018, from rheumatology clinics. Inclusion criteria were Bay Area residency; oral fluency in English, Spanish, Cantonese, or Mandarin; 18 years or older; ability to provide informed consent; and a physician confirmed SLE diagnosis. Food, housing, health care, and financial economic insecurities were assessed by validated screening tools. Patient-reported outcomes were obtained using PROMIS, Quality of Life in Neurological Disorders (known as Neuro-QoL) Cognitive Function short form, Patient Health Questionnaire (PHQ)-8, and General Anxiety Disorder (GAD)-7 instruments. Poverty was defined as household income of 125% or less of the federal poverty limit. Lower education was defined as less than college-graduate education. The association of economic insecurities with patient-reported outcomes was assessed by multivariable linear regression models adjusting for demographics, SLE disease characteristics, and comorbidities. We tested for interactions of insecurities with poverty and education. FINDINGS: The final cohort included 252 participants. Mean age was 49·7 (SD 13·4) years, 228 (90%) of 252 were women and 24 (10%) were men. 80 (32%) individuals self-identified as Asian, 26 (10%) as Black, 101 (40%) as White, eight (3%) as mixed race, and 37 (15%) as other race; 59 (23%) self-identified as Hispanic. 135 (54%) individuals had at least one insecurity. Insecurities were highly prevalent, and more common in those with poverty and lower education. Adjusted multivariate analyses revealed that participants with any insecurity had significantly worse scores across all measured patient-reported outcomes. For physical function, no insecurity had an adjusted mean score of 48·9 (95% CI 47·5-50·3) and any insecurity had 45·7 (44·3-47·0; p=0·0017). For pain interference, no insecurity was 52·0 (50·5-53·5) and any insecurity was 54·4 (53·0-55·8; p=0·031). For fatigue, no insecurity was 50·5 (48·8-52·3) and any insecurity was 54·9 (53·3-56·5; p=0·0005). For sleep disturbance, no insecurity was 49·9 (48·3-51·6) and any insecurity was 52·9 (51·4-54·5; p=0·012). For cognitive function, no insecurity was 49·3 (47·7-50·9) and any insecurity was 45·6 (44·1-47·0; p=0·0011). For PHQ-8, no insecurity was 4·4 (3·6-5·1) and any insecurity was 6·1 (5·4-6·8; p=0·0013). For GAD-7, no insecurity was 3·3 (2·6-4·1) and any insecurity was 5·2 (4·5-5·9; p=0·0008). Individuals with more insecurities had worse patient-reported outcomes. There were no statistically significant interactions between insecurities and poverty or education. INTERPRETATION: Having any economic insecurity was associated with worse outcomes for people with SLE regardless of poverty or education. The findings of this study provide insight into the relationship between economic insecurities and SLE outcomes and underscore the need to assess whether interventions that directly address these insecurities can reduce health disparities in SLE. FUNDING: US Centers for Disease Control, Rheumatology Research Foundation, and National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Screening of Environmental Chemicals to Characterize Exposures in Participants With Systemic Lupus Erythematosus.

OBJECTIVE: There is a need to characterize exposures associated with the pathogenesis of systemic lupus erythematosus (SLE). In this pilot study, we explore a hypothesis-free approach that can measure thousands of exogenous chemicals in blood ("exposome") in patients with SLE and unaffected controls. METHODS: This cross-sectional study analyzed a cohort of patients with prevalent SLE (n = 285) and controls (n = 106). Plasma was analyzed by liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS). Mass spectrometry features present in at least 25% of all samples were selected for association analysis (n = 2,737). Features were matched to potential chemicals using available databases. Association analysis of abundances of features with SLE status was performed, adjusting for age and sex. We also explored features associated with SLE phenotypes, sociodemographic factors, and current medication use. RESULTS: We found 30 features significantly associated with SLE status (Bonferroni P < 0.05). Of these, seven matched chemical names based on databases. These seven features included phthalate metabolites, a formetanate metabolite, and eugenol. The abundance of acid pesticides differed between patients with SLE and controls (Bonferroni P < 0.05). Two unmatched features were associated with a history of lupus nephritis, and one with anti-double-stranded DNA antibody production (Bonferroni P < 0.05). Seventeen features varied by self-reported race and ethnicity, including a polyfluoroalkyl substance (analysis of variance P < 1.69 × 10-5). Eleven features correlated with antimalarials, 6 with mycophenolate mofetil, and 29 with prednisone use. CONCLUSION: This proof-of-concept study demonstrates that LC-QTOF/MS is a powerful tool that agnostically detects circulating exogenous compounds. These analyses can generate hypotheses of disease-related exposures for future prospective, longitudinal studies.

Positive psychosocial factors may protect against perceived stress in people with systemic lupus erythematosus with and without trauma history.

OBJECTIVE: Trauma history is associated with SLE onset and worse patient-reported outcomes; perceived stress is associated with greater SLE disease activity. Stress perceptions vary in response to life events and may be influenced by psychosocial factors. In an SLE cohort, we examined whether stressful events associated with perceived stress, whether psychosocial factors affected perceived stress, and whether these relationships varied by prior trauma exposure. METHODS: This is a cross-sectional analysis of data from the California Lupus Epidemiology Study, an adult SLE cohort. Multivariable linear regression analyses controlling for age, gender, educational attainment, income, SLE damage, comorbid conditions, glucocorticoids ≥7.5 mg/day and depression examined associations of recent stressful events (Life Events Inventory) and positive (resilience, self-efficacy, emotional support) and negative (social isolation) psychosocial factors with perceived stress. Analyses were stratified by lifetime trauma history (Brief Trauma Questionnaire (BTQ)) and by adverse childhood experiences (ACEs) in a subset. RESULTS: Among 242 individuals with SLE, a greater number of recent stressful events was associated with greater perceived stress (beta (95% CI)=0.20 (0.07 to 0.33), p=0.003). Positive psychosocial factor score representing resilience, self-efficacy and emotional support was associated with lower perceived stress when accounting for number of stressful events (-0.67 (-0.94 to -0.40), p<0.0001); social isolation was associated with higher stress (0.20 (0.14 to 0.25), p<0.0001). In analyses stratified by BTQ trauma and ACEs, associations of psychosocial factors and perceived stress were similar between groups. However, the number of recent stressful events was significantly associated with perceived stress only for people with BTQ trauma (0.17 (0.05 to 0.29), p=0.0077) and ACEs (0.37 (0.15 to 0.58), p=0.0011). CONCLUSION: Enhancing positive and lessening negative psychosocial factors may mitigate deleterious perceived stress, which may improve outcomes in SLE, even among individuals with a history of prior trauma who may be more vulnerable to recent stressful events.

Disease-modifying therapies in systemic lupus erythematosus for extrarenal manifestations.

Our 2022 published working definition of disease modification in systemic lupus erythematosus (SLE) was 'minimising disease activity with the fewest treatment-associated toxicities and slowing or preventing organ damage progression'. The objective of this review was to classify current SLE treatments according to the proposed non-renal disease modification criteria excluding toxicities. Based on a review of select clinical trial (n=32) and observational study (n=54) publications for 14 SLE medications across different therapeutic classes, and the authors' clinical experience, we evaluated disease modification potential as per the proposed framework at three time points. Specific criteria used to determine disease modification potential included a drug's capacity to reduce: (1) non-renal disease activity, (2) severe flares, (3) use of steroids/immunosuppressants and (4) organ damage accrual. Criteria 1-3 were assessed at 1 year and 2-5 years and, when positive, were considered evidence for disease modification potential; criterion 4 was used to confirm disease modification at >5 years. Each treatment received one of four mutually exclusive designations at each time point: (a) criterion met, (b) indications of criterion met despite insufficient evidence in the literature, (c) inconclusive and (d) no available supportive data. This review excludes an assessment of potential toxicities. Eight of the 14 SLE treatments met ≥1 disease modification criteria up to year 5. Hydroxychloroquine improved overall survival at >5 years, suggesting long-term disease modification, but no data on specific organ systems were reported. Belimumab was the only treatment to meet all criteria. Belimumab and hydroxychloroquine met disease modification definitions across three time points. Evidence for other SLE therapies was incomplete, particularly at >5 years. Future studies are warranted for other treatments to meet the disease modification criteria. We discuss challenges to classification and possible updates to our published criteria.

Cell-Specific Transposable Element and Gene Expression Analysis Across Systemic Lupus Erythematosus Phenotypes.

OBJECTIVE: There is an established yet unexplained link between interferon (IFN) and systemic lupus erythematosus (SLE). The expression of sequences derived from transposable elements (TEs) may contribute to SLE phenotypes, specifically production of type I IFNs and generation of autoantibodies. METHODS: We profiled cell-sorted RNA-sequencing data (CD4+ T cells, CD14+ monocytes, CD19+ B cells, and natural killer cells) from peripheral blood mononuclear cells of 120 patients with SLE and quantified TE expression identifying 27,135 TEs. We tested for differential TE expression across 10 SLE phenotypes, including autoantibody production and disease activity. RESULTS: We found 731 differentially expressed (DE) TEs across all SLE phenotypes that were mostly cell specific and phenotype specific. DE TEs were enriched for specific families and open reading frames of viral genes encoded in TE sequences. Increased expression of DE TEs was associated with genes involved in antiviral activity, such as LY6E, ISG15, and TRIM22, and pathways such as IFN signaling. CONCLUSION: These findings suggest that expression of TEs contributes to activation of SLE-related mechanisms in a cell-specific manner, which can impact disease diagnostics and therapeutics.

Impact of Glucocorticoid Dose on Complete Response, Serious Infections, and Mortality During the Initial Therapy of Lupus Nephritis: A Systematic Review and Meta-Analysis of the Control Arms of Randomized Controlled Trials.

OBJECTIVE: Our objective was to evaluate the effect of glucocorticoid regimens on renal response, infections, and mortality among patients with lupus nephritis (LN). METHODS: We performed a systematic review and meta-analysis of the control arms of randomized clinical trials (RCTs). We included RCTs of biopsy-proven LN that used a protocolized regimen of glucocorticoids in combination with mycophenolic acid analogs or cyclophosphamide and reported the outcomes of complete response (CR), serious infections, and death. The starting dosage of glucocorticoids, tapering method, and administration of glucocorticoid pulses were abstracted. Meta-analysis of proportions, meta-regression, and subgroup meta-analysis were performed at 6 and 12 months for all outcomes. RESULTS: Fifty RCT arms (3,231 patients with LN) were included. The predicted rates of CR, serious infections, and death when starting on oral prednisone at 25 mg/day without pulses were 19.5% (95% confidence interval [CI] 7.3-31.5), 3.2% (95% CI 2.4-4.0), and 0.2% (95% CI 0.0-0.4), respectively. Starting on prednisone at 60 mg/day (without pulses) increased the rates to 34.6% (95% CI 16.9-52.3), 12.1% (95% CI 9.3-14.9), and 2.7% (95% CI 0.0-5.3), respectively. Adding glucocorticoid pulses increased the rates of CR and death but not serious infections. We observed a dose-response gradient between the initial glucocorticoid dosage and all the outcomes at six months after accounting for the administration of glucocorticoid pulses, underlying immunosuppressant, and baseline proteinuria. CONCLUSION: A higher exposure to glucocorticoids during the initial therapy of LN was associated with better renal outcomes at the cost of increased infections and death.

Longitudinal patterns and predictors of response to standard-of-care therapy in lupus nephritis: data from the Accelerating Medicines Partnership Lupus Network.

BACKGROUND: Leveraging the Accelerating Medicines Partnership (AMP) Lupus Nephritis (LN) dataset, we evaluated longitudinal patterns, rates, and predictors of response to standard-of-care therapy in patients with lupus nephritis. METHODS: Patients from US academic medical centers with class III, IV, and/or V LN and a baseline urine protein/creatinine (UPCR) ratio ≥ 1.0 (n = 180) were eligible for this analysis. Complete response (CR) required the following: (1) UPCR < 0.5; (2) normal serum creatinine (≤ 1.3 mg/dL) or, if abnormal, ≤ 125% of baseline; and (3) prednisone ≤ 10 mg/day. Partial response (PR) required the following: (1) > 50% reduction in UPCR; (2) normal serum creatinine or, if abnormal, ≤ 125% of baseline; and (3) prednisone dose ≤ 15 mg/day. RESULTS: Response rates to the standard of care at week 52 were CR = 22.2%; PR = 21.7%; non-responder (NR) = 41.7%, and not determined (ND) = 14.4%. Only 8/180 (4.4%) patients had a week 12 CR sustained through week 52. Eighteen (10%) patients attained a week 12 PR or CR and sustained their responses through week 52 and 47 (26.1%) patients achieved sustained PR or CR at weeks 26 and 52. Week 52 CR or PR attainment was associated with baseline UPCR > 3 (ORadj = 3.71 [95%CI = 1.34-10.24]; p = 0.012), > 25% decrease in UPCR from baseline to week 12 (ORadj = 2.61 [95%CI = 1.07-6.41]; p = 0.036), lower chronicity index (ORadj = 1.33 per unit decrease [95%CI = 1.10-1.62]; p = 0.003), and positive anti-dsDNA antibody (ORadj = 2.61 [95%CI = 0.93-7.33]; p = 0.069). CONCLUSIONS: CR and PR rates at week 52 were consistent with the standard-of-care response rates observed in prospective registrational LN trials. Low sustained response rates underscore the need for more efficacious therapies and highlight how critically important it is to understand the molecular pathways associated with response and non-response.

Mycophenolate mofetil withdrawal in patients with systemic lupus erythematosus: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Mycophenolate mofetil is an immunosuppressant commonly used to treat systemic lupus erythematosus (SLE) and lupus nephritis. It is a known teratogen associated with significant toxicities, including an increased risk of infections and malignancies. Mycophenolate mofetil withdrawal is desirable once disease quiescence is reached, but the timing of when to do so and whether it provides a benefit has not been well-studied. We aimed to determine the effects of mycophenolate mofetil withdrawal on the risk of clinically significant disease reactivation in patients with quiescent SLE on long-term mycophenolate mofetil therapy. METHODS: This multicenter, open-label, randomised trial was conducted in 19 centres in the USA. Eligible patients were aged between 18 and 70 years old, met the American College of Rheumatology (ACR) 1997 SLE criteria, and had a clinical SLEDAI score of less than 4 at screening. Mycophenolate mofetil therapy was required to be stable or decreasing for 2 years or more if initiated for renal indications, or for 1 year or more for non-renal indications. Participants were randomly allocated in a 1:1 ratio to a withdrawal group, who tapered off mycophenolate mofetil over 12 weeks, or a maintenance group who maintained their baseline dose (1-3g per day) for 60 weeks. Adaptive random allocation ensured groups were balanced for study site, renal versus non-renal disease, and baseline mycophenolate mofetil dose (≥2 g per day vs <2 g per day). Clinically significant disease reactivation by week 60 following random allocation, requiring increased doses or new immunosuppressive therapy was the primary endpoint, in the modified intention-to-treat population (all randomly allocated participants who began study-provided mycophenolate mofetil). Non-inferiority was evaluated using an estimation-based approach. The trial was registered at ClinicalTrials.gov (NCT01946880) and is completed. FINDINGS: Between Nov 6, 2013, and April 27, 2018, 123 participants were screened, of whom 102 were randomly allocated to the maintenance group (n=50) or the withdrawal group (n=52). Of the 100 participants included in the modified intention-to-treat analysis (49 maintenance, 51 withdrawal), 84 (84%) were women, 16 (16%) were men, 40 (40%) were White, 41 (41%) were Black, and 76 (76%) had a history of lupus nephritis. The average age was 42 (SD 12·7). By week 60, nine (18%) of 51 participants in the withdrawal group had clinically significant disease reactivation, compared to five (10%) of 49 participants in the maintenance group. The risk of clinically significant disease reactivation was 11% (95% CI 5-24) in the maintenance group and 18% (10-32) in the withdrawal group. The estimated increase in the risk of clinically significant disease reactivation with mycophenolate mofetil withdrawal was 7% (one-sided upper 85% confidence limit 15%). Similar rates of adverse events were observed in the maintenance group (45 [90%] of 50 participants) and the withdrawal group (46 [88%] of 52 participants). Infections were more frequent in the mycophenolate mofetil maintenance group (32 [64%]) compared with the withdrawal group (24 [46%]). INTERPRETATIONS: Mycophenolate mofetil withdrawal is not significantly inferior to mycophenolate mofetil maintenance. Estimates for the rates of disease reactivation and increases in risk with withdrawal can assist clinicians in making informed decisions on withdrawing mycophenolate mofetil in patients with stable SLE. FUNDING: The National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis.

Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL-16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.

Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis.

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 pathologic 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 in patients with LN and to identify correlates of renal parameters and treatment response. Unbiased analysis identified 3 immunologically distinct groups of patients with LN 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 at baseline showed more severe 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 primarily by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive by immunophenotyping at enrollment but with chronic renal injuries. Main immune profiles could be distilled down to 5 simple cytometric parameters that recapitulate several of the associations, highlighting the potential for blood immune profiling to translate to clinically useful non-invasive metrics to assess immune-mediated disease in LN.

Efficacy of anifrolumab across organ domains in patients with moderate-to-severe systemic lupus erythematosus: a post-hoc analysis of pooled data from the TULIP-1 and TULIP-2 trials.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by multisystem involvement. We aimed to evaluate the efficacy of anifrolumab on organ domain-specific SLE disease activity. METHODS: In this post-hoc analysis, data were pooled from the randomised, placebo-controlled, phase 3 TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) trials of anifrolumab (300 mg intravenously once every 4 weeks for 48 weeks) in patients aged 18-70 years with moderate-to-severe SLE. We evaluated changes from baseline to week 52 in British Isles Lupus Assessment Group 2004 (BILAG-2004) and SLE Disease Activity Index 2000 (SLEDAI-2K) organ domain scores, Cutaneous Lupus Erythematosus Disease Area and Severity Index activity score (CLASI-A), swollen and tender joint counts, haematology, and serology. FINDINGS: Among the 726 patients included, the mean age was 41·8 years (SD 11·9); 674 (93%) were female, 52 (7%) were male, and 479 (66%) were White. 360 patients received anifrolumab 300 mg (180 patients in each trial), and 366 received placebo (184 patients in TULIP-1 and 182 patients in TULIP-2). The most frequently affected organ domains at baseline were musculoskeletal (645 [89%] patients based on BILAG-2004; 684 [94%] with SLEDAI-2K) and mucocutaneous (627 [86%] with BILAG-2004; 699 [96%] based on SLEDAI-2K). At week 52, anifrolumab treatment resulted in greater improvements versus placebo in the musculoskeletal system (176 [56%] of 317 patients vs 143 [44%] of 328 with BILAG-2004; 164 [49%] of 335 vs 141 [40%] of 349 with SLEDAI-2K), the mucocutaneous system (168 [54%] of 315 vs 119 [38%] of 312 with BILAG-2004; 190 [55%] of 348 vs 138 [39%] of 351 SLEDAI-2K), and immunological system (44 [19%] of 237 vs 26 [11%] of 230 with SLEDAI-2K). Less frequently affected domains had varied responses. Among patients with a CLASI-A of 10 or more at baseline, greater proportions of patients receiving anifrolumab than placebo achieved a reduction of 50% or more in CLASI-A at week 52 (49 [46%] of 107 vs 24 [25%] of 94). Among patients with at least six swollen joints, more patients in the anifrolumab group than in the placebo group had a 50% or more reduction from baseline to week 52 in swollen joint count (99 [57%] of 174 vs 92 [46%] of 200), but the difference between groups was not significant for 50% or more reduction in tender joint count. INTERPRETATION: Across the two pivotal phase 3 trials, anifrolumab treatment improved SLE disease activity across multiple organ domains. FUNDING: AstraZeneca.