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Objective To identify determinants of neuropsychiatric (NP) flares in patients with systemic lupus erythematosus (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 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.

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.

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.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.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.

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.

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(-)CD27(bright) 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(-)CD24(bright)CD38(bright) 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. Funding Agencies|Swedish Rheumatism Association [R-969696]; King Gustaf Vs 80-year Foundation [FAI-2020-0741, FAI-2020-0663]; Swedish Society of Medicine [SLS-974449]; Nyckelfonden [OLL-974804]; Professor Nanna Svartz Foundation [2020-00368]; Ulla and Roland Gustafsson Foundation [2021-26]; Region Stockholm [FoUI-955483]; Karolinska Institutet

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.

Lupus nephritis (LN) is a major cause of morbidity and mortality among patients with systemic lupus erythematosus (SLE). However, promising emerging biomarkers pave the way toward an improved management of patients with LN. We have reviewed the literature over the past decade, and we herein summarise the most relevant biomarkers for diagnosis, monitoring, and prognosis in LN. An initial systematic search of Medline was conducted to identify pertinent articles. A total of 104 studies were selected to be included in this review. Several diagnostic biomarkers, including MCP-1, TWEAK, NGAL, and uric acid, exhibited good ability to differentiate LN patients from non-renal SLE patients. Several cytokines and chemokines, including IL-10, IL-17, MCP-1, and IP-10, hold promise for assessing LN disease activity, as do cell adhesion molecules (CAMs). Angiogenesis-related and haemostasis-related proteins have also displayed potential for monitoring disease activity. Biomarkers of responses to therapy include Axl, CD163, and BAFF, whereas VCAM-1, ALCAM, and ANCAs have been reported as prognostic markers, along with traditional markers. In addition, novel renal tissue biomarkers may prove to be a useful complement to histological evaluations. The overall heterogeneity of the inclusion criteria and outcome measures across different studies, along with a lack of validation in multi-centre cohorts, call for future collaborative efforts. Nevertheless, we foresee that several biomarkers hold promise toward optimisation of the management of LN, with the use of integrated omics and panels of less invasive biomarkers paving the way towards personalised medicine.

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., The Swedish Rheumatism Association (R-941095), King Gustaf V’s 80-year Foundation (FAI-2020-0741), Swedish Society of Medicine (SLS-974449), Nyckelfonden (OLL-974804), Ulla and Roland Gustafsson Foundation (2021–26), Region Stockholm (FoUI-955483), Karolinska Institutet, Innovative Medicines Initiative (IMI) Joint Undertaking (JU) for the PRECISESADS project (grant number 115565), IMI 2 JU for the 3 TR project (grant number 831434), EU Horizon 2020

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 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 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.

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 (β = 0.60) or four consecutive (β = 0.66) visits in remission were required to achieve a benefit ≥MCID in SF-36 physical component summary (PCS) scores, and six cumulative (β = 0.44) or five consecutive (β = 0.49) for a benefit ≥MCID in mental component summary (MCS) scores. Eight cumulative (β = 0.30 for both) or eight consecutive (β = 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 (β = 0.007) or five consecutive (β = 0.008) visits in remission were required, and eight cumulative (β = 0.005) or six consecutive (β = 0.006) visits in LLDAS. For FACIT-Fatigue scores ≥MCID, 12 cumulative (β = 0.34) or 10 consecutive (β = 0.39) visits in remission were required, and 17 cumulative (β = 0.24) or 16 consecutive (β = 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.

To investigate changes in B cell subsets in relation to disease flares upon initiation of standard therapy (ST) plus belimumab or placebo in patients with systemic lupus erythematosus (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) changes in peripheral B cell subsets, anti-dsDNA and complement levels with the occurrence of disease flares from week 24 through week 52 (Mann-WhitneyPatients on ST alone who flared displayed less prominent early decreases in CD19Increase or lack of decrease in certain circulating B cell subsets or anti-dsDNA levels upon treatment initiation for active SLE heralded subsequent severe disease flares. A rapid expansion of memory B cells may signify sustained response to therapy when followed by a subsequent drop, while no return or delayed increases in memory B cells may portend flaring. Peripheral B cell and serological marker kinetics may help identify patients in whom therapeutic modifications could protect against flare development, and may hence prove a useful complement to traditional surveillance and early treatment evaluation in SLE.

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.