Molecular characterisation of lupus low disease activity state (LLDAS) and DORIS remission by whole-blood transcriptome-based pathways in a pan-European systemic lupus erythematosus cohort.

OBJECTIVES: To unveil biological milieus underlying low disease activity (LDA) and remission versus active systemic lupus erythematosus (SLE). METHODS: We determined differentially expressed pathways (DEPs) in SLE patients from the PRECISESADS project (NTC02890121) stratified into patients fulfilling and not fulfilling the criteria of (1) Lupus LDA State (LLDAS), (2) Definitions of Remission in SLE remission, and (3) LLDAS exclusive of remission. RESULTS: We analysed data from 321 patients; 40.8% were in LLDAS, and 17.4% in DORIS remission. After exclusion of patients in remission, 28.3% were in LLDAS. Overall, 604 pathways differed significantly in LLDAS versus non-LLDAS patients with an false-discovery rate-corrected p (q)<0.05 and a robust effect size (dr)≥0.36. Accordingly, 288 pathways differed significantly between DORIS remitters and non-remitters (q<0.05 and dr≥0.36). DEPs yielded distinct molecular clusters characterised by differential serological, musculoskeletal, and renal activity. Analysis of partially overlapping samples showed no DEPs between LLDAS and DORIS remission. Drug repurposing potentiality for treating SLE was unveiled, as were important pathways underlying active SLE whose modulation could aid attainment of LLDAS/remission, including toll-like receptor (TLR) cascades, Bruton tyrosine kinase (BTK) activity, the cytotoxic T lymphocyte antigen 4 (CTLA-4)-related inhibitory signalling, and the nucleotide-binding oligomerization domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome pathway. CONCLUSIONS: We demonstrated for the first time molecular signalling pathways distinguishing LLDAS/remission from active SLE. LLDAS/remission was associated with reversal of biological processes related to SLE pathogenesis and specific clinical manifestations. DEP clustering by remission better grouped patients compared with LLDAS, substantiating remission as the ultimate treatment goal in SLE; however, the lack of substantial pathway differentiation between the two states justifies LLDAS as an acceptable goal from a biological perspective.

Determinants of neuropsychiatric flares in patients with systemic lupus erythematosus: results from five phase III trials of belimumab.

OBJECTIVE: To identify determinants of neuropsychiatric (NP) flares in patients with SLE treated for active SLE yet no ongoing severe NPSLE with non-biologic standard therapy plus belimumab or placebo. METHODS: We analysed data from five phase III trials (BLISS-52, BLISS-76, BLISS-NEA, BLISS-SC, EMBRACE; n = 3638) after exclusion of patients with baseline NP BILAG A. Factors associated with NPSLE flare, defined as a new NP BILAG A or B, were investigated using Cox regression. In a subgroup analysis, we studied patients with baseline NP BILAG E for determinants of de novo NPSLE flare. Organ damage was assessed using the SLICC/ACR Damage Index (SDI). RESULTS: We documented 105 (2.9%) NPSLE flares. In multivariable analysis, male sex (HR = 2.37; 95% CI: 1.31, 4.28; P = 0.004), baseline NP BILAG B-D (HR = 5.91; 95% CI: 3.86, 9.06; P < 0.001), and increasing SDI scores (HR = 1.35; 95% CI: 1.21, 1.50; P < 0.001) were strongly associated with NPSLE flare. Belimumab use yielded no association at any dose or administration form. In analysis of SDI domains, NP damage was the strongest determinant of NPSLE flare (HR = 3.25; 95% CI: 2.72, 3.88; P < 0.001), holding true for cognitive impairment (HR = 14.29; 95% CI: 9.22, 22.14; P < 0.001), transverse myelitis (HR = 21.89; 95% CI: 5.40, 88.72; P < 0.001), and neuropathy (HR = 8.87; 95% CI: 5.59, 14.09; P < 0.001). Male sex was the strongest determinant of de novo NPSLE flare (HR = 3.26; 95% CI: 1.51, 7.04; P = 0.003). CONCLUSION: Male sex, NPSLE history, and NP damage were strong determinants of impending NPSLE flare. No clear protection or predisposition was conferred from add-on belimumab.

Patients with neuropsychiatric involvement systemic lupus erythematosus experience poorer health-related quality of life and more fatigue than systemic lupus erythematosus patients with no neuropsychiatric involvement, irrespective of neuropsychiatric activity.

OBJECTIVES: Substantial proportions of patients with systemic lupus erythematosus (SLE) report poor health-related quality of life (HRQoL). Our objective was to investigate the impact of neuropsychiatric involvement (NP) in SLE on patient-reported outcomes. METHODS: We analysed data from four phase III trials (BLISS-52, BLISS-76, BLISS-SC, EMBRACE; N = 2968). The neuropsychiatric SLE (NPSLE) group comprised individuals with NP-British Isles Lupus Assessment group (BILAG) A/B/C/D or score in any descriptor of the NP-SLEDAI-2K at baseline (N = 350), while the non-NPSLE group consisted of patients with NP-BILAG E (N = 2618). HRQoL was assessed with the SF-36, EQ-5D-3L, and FACIT-F. Full health state (FHS) was defined as "no problems" in all EQ-5D dimensions. RESULTS: NPSLE patients reported lower scores in the SF-36 physical and mental component summary compared with the non-NPSLE population (mean±s.d.: 35.7±9.1 versus 39.6±9.6; p<0.001 and 37.3±12.1 versus 41.4±11.0; p<0.001, respectively). NPSLE patients also exhibited impaired HRQoL in all EQ-5D dimensions compared with non-NPSLE patients (p<0.05 for all). A substantially lower proportion among NPSLE patients experienced FHS in comparison with the non-NPSLE group (3.3% versus 14.5%; p<0.001). NPSLE was associated with severe fatigue (23.8±12.2 versus 31.5±11.6; p<0.001). Notably, our findings revealed no discernible distinctions between active and inactive NPSLE patients with regard to SF-36, EQ-5D, FHS, and FACIT-F scores. CONCLUSION: Neuropsychiatric involvement in patients with SLE has a detrimental effect on HRQoL experience and is associated with severe fatigue, regardless of the degree of neuropsychiatric disease activity. Early intervention is warranted in NPSLE patients to enhance long-term HRQoL experience.

Molecular architecture of proliferative lupus nephritis as elucidated using 50-plex imaging mass cytometry proteomics.

Due to unique advantages that allow high-dimensional tissue profiling, we postulated imaging mass cytometry (IMC) may shed novel insights on the molecular makeup of proliferative lupus nephritis (LN). This study interrogates the spatial expression profiles of 50 target proteins in LN and control kidneys. Proliferative LN glomeruli are marked by podocyte loss with immune infiltration dominated by CD45RO+, HLA-DR+ memory CD4 and CD8 T-cells, and CD163+ macrophages, with similar changes in tubulointerstitial regions. Macrophages are the predominant HLA-DR expressing antigen presenting cells with little expression elsewhere, while macrophages and T-cells predominate cellular crescents. End-stage sclerotic glomeruli are encircled by an acellular fibro-epithelial Bowman's space surrounded by immune infiltrates, all enmeshed in fibronectin. Proliferative LN also shows signs indicative of epithelial to mesenchymal plasticity of tubular cells and parietal epithelial cells. IMC enabled proteomics is a powerful tool to delineate the spatial architecture of LN at the protein level.

Distinct gene dysregulation patterns herald precision medicine potentiality in systemic lupus erythematosus.

OBJECTIVES: We aimed at investigating the whole-blood transcriptome, expression quantitative trait loci (eQTLs), and levels of selected serological markers in patients with SLE versus healthy controls (HC) to gain insight into pathogenesis and identify drug targets. METHODS: We analyzed differentially expressed genes (DEGs) and dysregulated gene modules in a cohort of 350 SLE patients and 497 HC from the European PRECISESADS project (NTC02890121), split into a discovery (60%) and a replication (40%) set. Replicated DEGs qualified for eQTL, pathway enrichment, regulatory network, and druggability analysis. For validation purposes, a separate gene module analysis was performed in an independent cohort (GSE88887). RESULTS: Analysis of 521 replicated DEGs identified multiple enriched interferon signaling pathways through Reactome. Gene module analysis yielded 18 replicated gene modules in SLE patients, including 11 gene modules that were validated in GSE88887. Three distinct gene module clusters were defined i.e., "interferon/plasma cells", "inflammation", and "lymphocyte signaling". Predominant downregulation of the lymphocyte signaling cluster denoted renal activity. By contrast, upregulation of interferon-related genes indicated hematological activity and vasculitis. Druggability analysis revealed several potential drugs interfering with dysregulated genes within the "interferon" and "PLK1 signaling events" modules. STAT1 was identified as the chief regulator in the most enriched signaling molecule network. Drugs annotated to 15 DEGs associated with cis-eQTLs included bortezomib for its ability to modulate CTSL activity. Belimumab was annotated to TNFSF13B (BAFF) and daratumumab was annotated to CD38 among the remaining replicated DEGs. CONCLUSIONS: Modulation of interferon, STAT1, PLK1, B and plasma cell signatures showed promise as viable approaches to treat SLE, pointing to their importance in SLE pathogenesis.

Sensitivity analysis of EQ-5D-3L index scores in terms of discriminative and known-groups validity in SLE: introducing Adequate Health State.

OBJECTIVES: To investigate the ability of different EuroQol 5-Dimensions 3-Levels (EQ-5D-3L) index scores to discriminate between verum drug and placebo (discriminant validity) as well as between responders and non-responders (known-groups validity) in the SLE patient population of two phase III clinical trials of belimumab. METHODS: Data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials (N = 1684), which both showed superiority of belimumab to placebo, were utilized. Responders were defined as SLE Responder Index 4 (SRI-4) achievers at week 52. The Pearson's χ2 and Mann-Whitney U tests were used for comparisons, and logistic regression analysis was used for adjustments for confounders and assessment of independence. RESULTS: While full health state (FHS; EQ-5D index score 1) showed the best ability to discriminate between belimumab and placebo [adjusted odds ratio (OR) 1.47; 95% CI 1.11, 1.96; P = 0.008] and between SRI-4 responders and non-responders (adjusted OR 3.47; 95% CI 1.29, 10.98; P = 0.020), the discriminative ability of EQ-5D index scores 0.800 or more reached statistical significance for both discriminant validity (adjusted OR 1.29; 95% CI 1.02, 1.63; P = 0.036) and known-groups validity (adjusted OR 3.08; 95% CI 1.16, 9.69; P = 0.034). CONCLUSION: Overall, higher EQ-5D index scores were associated with increasing ability to discriminate between belimumab and placebo, and between responders and non-responders. EQ-5D index scores less stringent than FHS may be clinically relevant health-related quality of life goals of treatment in patients with SLE, introducing the concept of EQ-5D adequate health state when FHS is not achievable.

COVID-19 vaccination in autoimmune diseases (COVAD) study: vaccine safety and tolerance in rheumatoid arthritis.

OBJECTIVES: The COVID-19 vaccination in autoimmune diseases (COVAD) study aimed to assess short-term COVID-19 vaccination-related adverse events (AEs) in RA patients. METHODS: An online self-reported questionnaire (March-December 2021) was used to capture data related to COVID-19 vaccination-related AEs in RA, other autoimmune rheumatic diseases (AIRDs) (excluding RA and inflammatory myositis), non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs). Descriptive and multivariable regression analyses were performed. RESULTS: Of the 9462 complete respondents, 14.2% (n = 1347) had been diagnosed with RA; they had a mean (s.d.) age of 50.7 (13.7) years, 74.2% were women and 49.3% were Caucasian. In total, 76.9% and 4.2% of patients with RA reported minor and major AEs, respectively. Patients with active and inactive RA had similar AE and hospitalization frequencies. Overall, AEs were reported more frequently by BNT162b2 and mRNA-1273 recipients and less frequently by BBV152 recipients compared with the rest. Major AE and hospitalization frequencies were similar across recipients of different vaccines. Patients receiving methotrexate and hydroxychloroquine reported fewer minor AEs than those patients not on them. Compared with HCs and patients with other AIRDs, patients with RA reported similar total AEs, overall minor AEs, and hospitalizations. Compared with nrAIDs, patients with RA reported lower frequencies of overall AEs, minor AEs (both odds ratio [OR] = 0.7; 95% CI: 0.5, 0.9), and injection site pain (OR = 0.6; 95% CI: 0.5, 0.8) with similar major AE and hospitalization frequencies. CONCLUSION: Despite the differences in AE frequency across different COVID-19 vaccines, all were well tolerated in patients with RA and were comparable to HCs, providing reassurance as to the safety of COVID-19 vaccination.

Safety and tolerance of vaccines against SARS-CoV-2 infection in systemic lupus erythematosus: results from the COVAD study.

OBJECTIVE: To determine COVID-19 vaccine-related adverse events (AEs) in the seven-day post-vaccination period in patients with SLE vs autoimmune rheumatic diseases (AIRDs), non-rheumatic autoimmune diseases (nrAIDs), and healthy controls (HC). METHODS: Data were captured through the COVID-19 Vaccination in Autoimmune Diseases (COVAD) questionnaire (March-December 2021). Multivariable regression models accounted for age, gender, ethnicity, vaccine type and background treatment. RESULTS: Among 9462 complete respondents, 583 (6.2%) were SLE patients (mean age: 40.1 years; 94.5% females; 40.5% Asian; 42.9% Pfizer-recipients). Minor AEs were reported by 83.0% of SLE patients, major by 2.6%, hospitalization by 0.2%. AE and hospitalization frequencies were similar between patients with active and inactive SLE. Rashes were more frequent in SLE patients vs HC (OR; 95% CI: 1.2; 1.0, 1.5), chills less frequent in SLE vs AIRDs (0.6; 0.4, 0.8) and nrAIDs (0.5; 0.3, 0.8), and fatigue less frequent in SLE vs nrAIDs (0.6; 0.4, 0.9). Pfizer-recipients reported higher overall AE (2.2; 1.1, 4.2) and injection site pain (2.9; 1.6, 5.0) frequencies than recipients of other vaccines, Oxford/AstraZeneca-recipients more body ache, fever, chills (OR: 2.5, 3.0), Moderna-recipients more body ache, fever, chills, rashes (OR: 2.6, 4.3). Hospitalization frequencies were similar across vaccine types. AE frequencies were similar across treatment groups, although chills were less frequent in antimalarial users vs non-users (0.5; 0.3, 0.9). CONCLUSION: While COVID-19 vaccination-related AEs were reported by four-fifths of SLE patients, those were mostly minor and comparable to AEs reported by healthy individuals, providing reassurance regarding COVID-19 vaccination safety in SLE.

Diagnostic, predictive and prognostic biomarkers in systemic lupus erythematosus: current insights.

PURPOSE OF REVIEW: Biomarkers for diagnosis, monitoring and prognosis still constitute an unmet need for systemic lupus erythematosus (SLE). Focusing on recent findings, this review summarises the current landscape of biomarkers in lupus. RECENT FINDINGS: Urine activated leukocyte cell adhesion molecule (ALCAM) exhibited good diagnostic ability in SLE and lupus nephritis (LN) whereas cerebrospinal fluid neutrophil gelatinase-associated lipocalin (NGAL) showed promise in neuropsychiatric SLE. Urine ALCAM, CD163 and vascular cell adhesion molecule 1 (VCAM-1) may be useful in surveillance of LN. Urine monocyte chemoattractant protein 1 was found to predict treatment response in SLE, and urine CD163 and NGAL treatment response in LN. Serum complement component 3 (C3) and urinary VCAM-1 have been reported to portend long-term renal prognosis in LN. SUMMARY: NGAL holds promise as a versatile biomarker in SLE whereas urine ALCAM, CD163 and VCAM-1 displayed good performance as biomarkers in LN. The overall lack of concerted corroboration of leading candidates across multiple cohorts and diverse populations leaves the current biomarker landscape in SLE in an urgent need for further survey and systematic validation.

Impact of remission and low disease activity on health-related quality of life in patients with systemic lupus erythematosus.

OBJECTIVES: To investigate the impact of remission and lupus low disease activity state (LLDAS) on health-related quality of life (HRQoL) in systemic lupus erythematosus. METHODS: Short-Form 36 (SF-36), three-level EQ-5D (EQ-5D-3L) and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials were used. Duration in remission/LLDAS required to reach a HRQoL benefit ≥ minimal clinically important differences (MCIDs) during and post-treatment was determined using quantile regression and generalized estimating equations. RESULTS: Patients (n = 1684) were assessed every fourth week (15 visits). Four cumulative (ß = 0.60) or four consecutive (ß = 0.66) visits in remission were required to achieve a benefit ≥MCID in SF-36 physical component summary (PCS) scores, and six cumulative (ß = 0.44) or five consecutive (ß = 0.49) for a benefit ≥MCID in mental component summary (MCS) scores. Eight cumulative (ß = 0.30 for both) or eight consecutive (ß = 0.32 for both) visits in LLDAS were required for a benefit in PCS/MCS ≥MCID, respectively. For EQ-5D-3L index scores ≥MCID, six cumulative (ß = 0.007) or five consecutive (ß = 0.008) visits in remission were required, and eight cumulative (ß = 0.005) or six consecutive (ß = 0.006) visits in LLDAS. For FACIT-Fatigue scores ≥MCID, 12 cumulative (ß = 0.34) or 10 consecutive (ß = 0.39) visits in remission were required, and 17 cumulative (ß = 0.24) or 16 consecutive (ß = 0.25) visits in LLDAS. CONCLUSION: Remission and LLDAS contribute to a HRQoL benefit in a time-dependent manner. Shorter time in remission than in LLDAS was required for a clinically important benefit in HRQoL, and longer time in remission for a benefit in mental compared with physical HRQoL aspects. When remission/LLDAS was sustained, the same benefit was achieved in a shorter time.

The Volume Difference Along the External Surface of the Zygomatic Bone: A Novel Method of Measuring Zygomatic Bone Asymmetry.

ABSTRACT: This study introduced the volume difference along the external surface (VDAES) of the zygomatic bone as a novel approach to assess zygomatic bone asymmetry and was the first to describe a distinctive, 4-step method of measuring it. VDAES has a potential to be used as an objective tool to evaluate dislocation and can assist surgeons in predicting risks of long-term cosmetic complications in patients with zygomaticomaxillary complex fractures. After having measured 100 healthy study participants, the observed median VDAES was 1.48 cm3 for all study participants, 2.02 cm3 for males, and 1.09 cm3 for females, with the gender difference being significant (P = 0.003). Additional studies are needed to test the hypothesis of whether VDAES is more relevant than conventional methods of clinically evaluating zygomatic bone asymmetry.

B Cell Kinetics upon Therapy Commencement for Active Extrarenal Systemic Lupus Erythematosus in Relation to Development of Renal Flares: Results from Three Phase III Clinical Trials of Belimumab.

Renal flares constitute major determinants of poor prognosis in people living with systemic lupus erythematosus (SLE). The aim of the present study was to investigate changes in B cell subsets in relation to renal flares upon initiation of standard therapy (ST) plus belimumab or placebo in patients with SLE. Using data from the BLISS-76, BLISS-SC, and BLISS Northeast Asia trials, we investigated associations of relative to baseline rapid (through week 8) and early (through week 24) percentage changes in circulating CD19+ B cell subsets characterised through flow cytometry, anti-dsDNA antibodies, and complement levels with the occurrence of renal flares over one year. Patients who developed renal flares showed more prominent rapid decreases in CD19+CD20+CD138+ short-lived plasma cells (-50.4% vs. -16.7%; p = 0.019) and CD19+CD20-CD27bright plasmablasts (-50.0% vs. -29.9%; p = 0.020) compared to non-flaring patients, followed by a subsequent return. Less prominent rapid reductions in CD19+CD27-CD24brightCD38bright transitional B cells (-42.9% vs. -75.0%; p = 0.038) and CD19+CD20-CD138+ peripheral long-lived plasma cells (-11.3% vs. -29.2%; p = 0.019) were seen in belimumab-treated-but not placebo-treated-patients who developed renal flares compared to belimumab-treated patients who did not. Rapid and early changes in anti-dsDNA or complement levels showed no clear association with renal flares. In summary, a rapid drop followed by a subsequent return in circulating short-lived plasma cells and plasmablasts upon treatment for active extra-renal SLE portended renal flares, indicating a need for therapeutic adjustments in patients showing such B cell patterns. Rapid decreases in transitional B cells and peripheral long-lived plasma cells upon belimumab therapy commencement may signify a greater protection against renal flares. B cell kinetics may prove useful in early drug evaluation.

Contribution of abnormal BMI to adverse health-related quality of life outcomes after a 52-week therapy in patients with SLE.

OBJECTIVES: To investigate whether abnormal BMI is associated with adverse health-related quality of life (HRQoL) outcome, including severe fatigue, after 52 weeks of standard therapy plus belimumab or placebo in patients with SLE. METHODS: We analysed data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials (n = 1684). Adverse HRQoL was defined as SF-36 scores ≤ the fifth percentile in age- and sex-matched US population-based subjects, and FACIT-F scores <30. We compared BMI groups using the Pearson's χ2 test, and assessed independence with multivariable logistic regression analysis. RESULTS: Overweight (BMI ≥25 kg/m2) and obese (BMI ≥30 kg/m2) patients showed increased likelihood to exhibit adverse SF-36 physical component summary (OR: 1.8; 95% CI: 1.4, 2.3; P <0.001 and OR: 2.4; 95% CI: 1.8, 3.2; P <0.001, respectively) and FACIT-F (OR: 1.3; 95% CI: 1.1, 1.6; P = 0.010 and OR: 1.5; 95% CI: 1.2, 2.0; P = 0.002, respectively) scores at week 52. Underweight was associated with adverse SF-36 mental component summary scores, also after adjustment for sex, ancestry, age, disease duration, disease activity, organ damage and prednisone dose during the study period (OR: 2.1; 95% CI: 1.2, 3.6; P = 0.007). Addition of belimumab to standard therapy independently protected against adverse SF-36 general health (OR: 0.8; 95% CI: 0.6, 1.0; P = 0.025) and FACIT-F < 30 (OR: 0.8; 95% CI: 0.6, 1.0; P = 0.018). CONCLUSION: Overweight and obesity contributed to adverse physical and mental HRQoL outcomes after therapeutic intervention in SLE patients, and underweight contributed to adverse mental HRQoL outcome. A protective effect of belimumab against adverse general health and severe fatigue was implicated.

EQ-5D-3L full health state discriminates between drug and placebo in clinical trials of systemic lupus erythematosus.

OBJECTIVES: The objectives of this study were to investigate the discriminative ability of EQ-5D-3L full health state (FHS) in clinical trials of SLE, and to identify factors associated with FHS after treatment. METHODS: Data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials of belimumab (N = 1684) were utilized. FHS was defined as a response of no problems in all five EQ-5D-3L dimensions, yielding an index score of 1. The Pearson's χ2 or Fisher's exact test was employed for comparisons, and logistic regression for adjustments and assessment of independence. RESULTS: We demonstrated higher EQ-5D-3L FHS frequencies among patients given standard therapy (ST) plus the licensed belimumab dose vs ST alone (26.1% vs 19.4%; P = 0.001; week 52), and within SRI-4 responders vs non-responders (27.0% vs 19.8%; P < 0.001; week 52) from weeks 36 to 52. In multivariable regression analysis, SLEDAI-2K (OR: 0.90; 95% CI: 0.87, 0.94; P < 0.001) and SLICC/ACR Damage Index (OR: 0.79; 95% CI: 0.69, 0.91; P = 0.001) scores were independently associated with lower FHS frequencies at week 52, while adding monthly infusions of belimumab 10 mg/kg to ST favoured FHS perception (OR: 1.60; 95% CI: 1.15, 2.24; P = 0.006). Add-on belimumab 10 mg/kg yielded higher FHS frequencies in antimalarial users vs non-users (29.9% vs 20.1%; P = 0.011), and in anti-dsDNA- and anti-Sm- positive vs negative patients (31.4% vs 13.4%; P < 0.001 and 33.0% vs 22.6%; P = 0.010, respectively), whereas no significant differences were observed in patients given ST alone. CONCLUSION: EQ-5D-3L FHS distinguished belimumab from placebo and responders from non-responders, and exhibited known-group validity in subgroup analysis. FHS may prove a useful patient-reported outcome in SLE studies.

Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis.

Introduction: Current therapeutic management of lupus nephritis (LN) fails to induce long-term remission in over 50% of patients, highlighting the urgent need for additional options. Methods: We analyzed differentially expressed genes (DEGs) in peripheral blood from patients with active LN (n = 41) and active nonrenal lupus (n = 62) versus healthy controls (HCs) (n = 497) from the European PRECISESADS project (NTC02890121), and dysregulated gene modules in a discovery (n = 26) and a replication (n = 15) set of active LN cases. Results: Replicated gene modules qualified for correlation analyses with serologic markers, and regulatory network and druggability analysis. Unsupervised coexpression network analysis revealed 20 dysregulated gene modules and stratified the active LN population into 3 distinct subgroups. These subgroups were characterized by low, intermediate, and high interferon (IFN) signatures, with differential dysregulation of the "B cell" and "plasma cells/Ig" modules. Drugs annotated to the IFN network included CC-motif chemokine receptor 1 (CCR1) inhibitors, programmed death-ligand 1 (PD-L1) inhibitors, and irinotecan; whereas the anti-CD38 daratumumab and proteasome inhibitor bortezomib showed potential for counteracting the "plasma cells/Ig" signature. In silico analysis demonstrated the low-IFN subgroup to benefit from calcineurin inhibition and the intermediate-IFN subgroup from B-cell targeted therapies. High-IFN patients exhibited greater anticipated response to anifrolumab whereas daratumumab appeared beneficial to the intermediate-IFN and high-IFN subgroups. Conclusion: IFN upregulation and B and plasma cell gene dysregulation patterns revealed 3 subgroups of LN, which may not necessarily represent distinct disease phenotypes but rather phases of the inflammatory processes during a renal flare, providing a conceptual framework for precision medicine in LN.

Serum profiling identifies CCL8, CXCL13, and IL-1RA as markers of active disease in patients with systemic lupus erythematosus.

Introduction: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease that presents a challenge for clinicians. To identify potential biomarkers for diagnosis and disease activity in SLE, we investigated a selected yet broad panel of cytokines and autoantibodies in patients with SLE, healthy controls (HC), and patients with other autoimmune diseases (AIDs). Methods: Serum samples from 422 SLE patients, 546 HC, and 1223 other AIDs were analysed within the frame of the European PRECISESADS project (NTC02890121). Cytokine levels were determined using Luminex panels, and autoantibodies using different immunoassays. Results: Of the 83 cytokines analysed, 29 differed significantly between patients with SLE and HC. Specifically, CCL8, CXCL13, and IL-1RA levels were elevated in patients with active, but not inactive, SLE versus HC, as well as in patients with SLE versus other AIDs. The levels of these cytokines also correlated with SLE Disease Activity Index 2000 (SLEDAI-2K) scores, among five other cytokines. Overall, the occurrence of autoantibodies was similar across SLEDAI-2K organ domains, and the correlations between autoantibodies and activity in different organ domains were weak. Discussion: Our findings suggest that, upon validation, CCL8, CXCL13, and IL-1RA could serve as promising serum biomarkers of activity in SLE.

Effect of Belimumab on Preventing de novo Renal Lupus Flares.

Introduction: Belimumab was recently approved for treating lupus nephritis (LN), yet de novo LN cases during belimumab treatment given for nonrenal causes have been reported. Identification of reliable signals of impending flare is imperative. Methods: We evaluated belimumab efficacy in preventing de novo renal flares and factors associated with renal flare occurrence in nephritis-naïve patients with systemic lupus erythematosus (SLE) who are receiving add-on belimumab or placebo in 5 phase 3 clinical trials using Cox regression analysis. Results: Of 1844 eligible patients, 136 (7.4%) developed a de novo renal flare during a 52-week long follow-up. Asian origin (Adjusted Hazard Ratio [HRadj]: 1.97; 95% confidence interval [CI]: 1.32-2.94; P = 0.001), positive baseline anti-double stranded DNA (anti-dsDNA) levels (HRadj: 1.32; 95% CI: 1.07-1.63; P = 0.008), and increasing mean prednisone dose during follow-up (HRadj: 1.03; 95% CI: 1.02-1.04; P < 0.001) were associated with de novo renal flares. Low-dose intravenous (IV) belimumab (1 mg/kg monthly) yielded a nearly 3-fold lower hazard of de novo renal flare (HRadj: 0.38; 95% CI: 0.20-0.73; P = 0.004). Subcutaneous (SC) belimumab (200 mg weekly) also yielded a lower hazard (HRadj.: 0.69; 95% CI: 0.54-0.88; P = 0.003). The labeled IV dose (10 mg/kg monthly) conferred no clear protection (HRadj.: 0.74; 95% CI: 0.50-1.09; P = 0.127). Conclusion: We corroborated the substantial vulnerability of the Asian SLE population to renal affliction. Add-on low-dose IV belimumab (1 mg/kg) and SC belimumab appeared protective against renal flares in nephritis-naïve patients with SLE. The approved IV dose (10 mg/kg) yielded no clear protection.

Obesity is associated with pain and impaired mobility despite therapy in systemic lupus erythematosus.

Objective: To investigate whether abnormal BMI is associated with health-related quality of life (HRQoL) impairments, defined as patient-reported problems within the different dimensions of the three-level EQ-5D (EQ-5D-3L), before and after treatment for active systemic lupus erythematosus (SLE). Patients and methods: We conducted a post-hoc analysis of data from two phase III clinical trials of belimumab in SLE, i.e., BLISS-52 (n = 865) and BLISS-76 (n = 819). Underweight was defined as BMI <18.5 kg/m2, normal weight as BMI ≥18.5 but <25 kg/m2, pre-obesity as BMI ≥25 but <30 kg/m2, and obesity as BMI ≥30 kg/m2. We investigated associations between BMI groups and problems (level 2 or 3) within each one of the five EQ-5D dimensions before treatment initiation and at week 52, using logistic regression analysis adjusting for age, ethnicity, disease activity, and glucocorticoid dose, and for the post-treatment analysis also for belimumab treatment and baseline EQ-5D-3L responses. Results: Of 1,684 patients included, 73 (4%) were classified as underweight, 850 (50%) as normal weight, 438 (26%) as pre-obese, and 323 (19%) as obese. At baseline, obesity was associated with mild to severe problems in all EQ-5D dimensions (p < 0.05 for all), yielding the strongest association with problems in mobility (adjusted odds ratio, aOR: 2.1; 95% confidence interval, CI: 1.6-2.8; p < 0.001). Pre-obesity was also associated with problems in mobility (aOR: 1.4; 95% CI: 1.1-1.8; p = 0.005). Post-intervention, obesity was associated with problems in mobility and pain/discomfort, and pre-obesity with problems in mobility and self-care (p < 0.05 for all). Conclusion: Our study adds to the evidence that high BMI negatively affects SLE patients' HRQoL, with obesity being associated with pain and impaired mobility despite therapy.

COVID-19 Vaccination-Related Delayed Adverse Events among Patients with Systemic Lupus Erythematosus.

BACKGROUND: The safety profile of COVID-19 vaccination is well documented, but hesitancy among people with immune-mediated inflammatory diseases, often immunocompromised, remains high, partially due to a scarcity of data on safety over a longer term. We herein aimed to assess delayed adverse events (DAEs) occurring >7 days after COVID-19 vaccination in systemic lupus erythematosus (SLE) versus other rheumatic autoimmune diseases (rAIDs), non-rheumatic AIDs (nrAIDs), and healthy controls (HCs). METHODS: Self-reported data were captured within the COVID-19 Vaccination in Autoimmune Diseases (COVAD)-2 online survey, which comprised >150 centres and responses from 106 countries, between February and June 2022. Logistic regression analysis adjusting for important confounders (age, sex, ethnicity) was used to compare groups. RESULTS: Of 7203 eligible individuals, 882 (12.2%) patients had SLE, 3161 (43.9%) patients had rAIDs, 426 (5.9%) patients had nrAIDs, and 2734 (38.0%) were HCs. SLE patients had a median age of 39 years (IQR: 31-50); 93.7% were women. SLE patients reported, more frequently, major DAEs (OR: 1.6; 95% CI: 1.2-2.0; p = 0.001) and hospitalisation (OR: 2.2; 95% CI: 1.4-3.4; p < 0.001) compared to HCs, severe rashes (OR: 2.4; 95% CI: 1.3-4.2; p = 0.004) compared to people with rAIDS, and hospitalisation (OR: 2.3; 95% CI: 1.1-4.9; p = 0.029) as well as several minor DAEs compared to people with nrAIDs. Differences were observed between vaccines in terms of frequency of major DAEs and hospitalisations, with the latter seen more frequently in patients receiving the Moderna vaccine. People with SLE with no autoimmune multimorbidity less frequently reported overall minor DAEs compared to SLE patients with comorbid nrAIDs (OR: 0.5; 95% CI: 0.3-1.0; p = 0.036). CONCLUSION: Hospitalisations post-vaccination were more frequent in SLE patients than in HCs. Monitoring of SLE patients following COVID-19 vaccination can help in identifying DAEs early, informing patients about expected DAEs, and supporting patients, especially those with autoimmune multimorbidity.