Search

Aleksander Lenert,1 Timothy B Niewold,2 Petar Lenert3 1Division of Rheumatology, University of Kentucky, Kentucky Clinic, Lexington, KY, 2Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, MN, 3Division of Immunology, Department of Internal Medicine, The University of Iowa, Iowa City, IA, USA Abstract: B cells in general and BAFF (B cell activating factor of the tumor necrosis factor [TNF] family) in particular have been primary targets of recent clinical trials in systemic lupus erythematosus (SLE). In 2011, belimumab, a monoclonal antibody against BAFF, became the first biologic agent approved for the treatment of SLE. Follow-up studies have shown excellent long-term safety and tolerability of belimumab. In this review, we critically analyze blisibimod, a novel BAFF-neutralizing agent. In contrast to belimumab that only blocks soluble BAFF trimer but not soluble 60-mer or membrane BAFF, blisibimod blocks with high affinity all three forms of BAFF. Furthermore, blisibimod has a unique structure built on four high-affinity BAFF-binding peptides fused to the IgG1-Fc carrier. It was tested in phase I and II trials in SLE where it showed safety and tolerability. While it failed to reach the primary endpoint in a recent phase II trial, post hoc analysis demonstrated its efficacy in SLE patients with higher disease activity. Based on these results, blisibimod is currently undergoing phase III trials targeting this responder subpopulation of SLE patients. The advantage of blisibimod, compared to its competitors, lies in its higher avidity for BAFF, but a possible drawback may come from its immunogenic potential and the anticipated loss of efficacy over time. Keywords: BAFF, APRIL, lupus, B cells, blisibimod

A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10(-4) < P < 4.15 × 10(-2)), where we further identified a five-marker haplotype (rs12141731-rs2949655-rs16859085-rs12144621-rs858554; G-G-A-G-A; P(hap) = 2.12 × 10(-5)) that exceeded the most associated single SNP rs858554 (minor allele frequency in controls = 13%; P = 4.99 × 10(-4), odds ratio = 1.32) in significance. Imputation and subsequent association analysis showed evidence of association (P < 0.05) at 27 additional SNPs within intron 1. Cross-ethnic meta-analysis, assuming an additive genetic model adjusted for population proportions, showed five SNPs with significant P-values (1.40 × 10(-3) < P< 3.97 × 10(-2)), with one (rs704848) remaining significant after Bonferroni correction (P(meta) = 2.66 × 10(-2)). Our study independently confirms and extends the association of SLE with CD247, which is shared by various autoimmune disorders and supports a common T-cell-mediated mechanism.

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in

OBJECTIVE: Interferon-alpha (IFNalpha) is a heritable risk factor for systemic lupus erythematosus (SLE). Genetic variation near IRF7 is implicated in SLE susceptibility. SLE-associated autoantibodies can stimulate IFNalpha production through the Toll-like receptor/IRF7 pathway. This study was undertaken to determine whether variants of IRF7 act as risk factors for SLE by increasing IFNalpha production and whether autoantibodies are important to this phenomenon. METHODS: We studied 492 patients with SLE (236 African American, 162 European American, and 94 Hispanic American subjects). Serum levels of IFNalpha were measured using a reporter cell assay, and single-nucleotide polymorphisms (SNPs) in the IRF7/PHRF1 locus were genotyped. RESULTS: In a joint analysis of European American and Hispanic American subjects, the rs702966 C allele was associated with the presence of anti-double-stranded DNA (anti-dsDNA) antibodies (odds ratio [OR] 1.83, P = 0.0069). The rs702966 CC genotype was only associated with higher serum levels of IFNalpha in European American and Hispanic American patients with anti-dsDNA antibodies (joint analysis P = 4.1 x 10(-5) in anti-dsDNA-positive patients and P = 0.99 in anti-dsDNA-negative patients). In African American subjects, anti-Sm antibodies were associated with the rs4963128 SNP near IRF7 (OR 1.95, P = 0.0017). The rs4963128 CT and TT genotypes were associated with higher serum levels of IFNalpha only in African American patients with anti-Sm antibodies (P = 0.0012). In African American patients lacking anti-Sm antibodies, an effect of anti-dsDNA-rs702966 C allele interaction on serum levels of IFNalpha was observed, similar to the other patient groups (overall joint analysis P = 1.0 x 10(-6)). In European American and Hispanic American patients, the IRF5 SLE risk haplotype showed an additive effect with the rs702966 C allele on IFNalpha level in anti-dsDNA-positive patients. CONCLUSION: Our findings indicate that IRF7/PHRF1 variants in combination with SLE-associated autoantibodies result in higher serum levels of IFNalpha, providing a biologic relevance for this locus at the protein level in human SLE in vivo. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Interferon-alpha (IFNalpha) has been implicated in the pathogenesis of juvenile dermatomyositis (DM). The aim of this study was to examine serum IFNalpha activity in a cohort of children with juvenile DM to determine relationships between IFNalpha and indicators of disease activity and severity. METHODS: Thirty-nine children with definite/probable juvenile DM were included in the study. Serum samples were obtained at the time of diagnosis from 18 untreated patients with juvenile DM. Second samples from 11 of these patients were obtained at 24 months, while they were receiving treatment, and third samples were obtained from 7 of these patients at 36 months. The remaining 21 children were studied 36 months after their initial diagnosis. Serum IFNalpha activity was measured using a functional reporter cell assay. RESULTS: Patients with juvenile DM had higher serum IFNalpha activity than both pediatric and adult healthy control subjects. In untreated patients, serum IFNalpha activity was positively correlated with serum muscle enzyme levels (P < 0.05 for creatine kinase, aspartate aminotransferase, and aldolase) and inversely correlated with the duration of untreated disease (P = 0.017). The tumor necrosis factor alpha -308A allele was associated with higher serum IFNalpha levels only in untreated patients (P = 0.030). At 36 months, serum IFNalpha levels were inversely correlated with muscle enzyme levels in those patients still requiring therapy and with the skin Disease Activity Score in those patients who had completed therapy (P = 0.002). CONCLUSION: Serum IFNalpha activity was associated with higher serum levels of muscle-derived enzymes and a shorter duration of untreated disease in patients with newly diagnosed juvenile DM and was inversely correlated with measures of chronic disease activity at 36 months postdiagnosis. These data suggest that IFNalpha could play a role in disease initiation in juvenile DM. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The C1858T polymorphism in PTPN22 has been associated with the risk of systemic lupus erythematosus (SLE) as well as multiple other autoimmune diseases. We have previously shown that high serum interferon-alpha (IFNalpha) activity is a heritable risk factor for SLE. The aim of this study was to determine whether the PTPN22 risk variant may shift serum cytokine profiles to higher IFNalpha activity, resulting in risk of disease. METHODS: IFNalpha was measured in 143 patients with SLE, using a functional reporter cell assay, and tumor necrosis factor alpha (TNFalpha) was measured by enzyme-linked immunosorbent assay. The rs2476601 single-nucleotide polymorphism in PTPN22 (C1858T) was genotyped in the same patients. Patients were grouped, using a clustering algorithm, into 4 cytokine groups (IFNalpha predominant, IFNalpha and TNFalpha correlated, TNFalpha predominant, and both IFNalpha and TNFalpha low). RESULTS: SLE patients carrying the risk allele of PTPN22 had higher serum IFNalpha activity than patients lacking the risk allele (P = 0.027). TNFalpha levels were lower in carriers of the risk allele (P = 0.030), and the risk allele was more common in patients in the IFNalpha-predominant and IFNalpha and TNFalpha-correlated groups as compared with patients in the TNFalpha-predominant and both IFNalpha and TNFalpha-low groups (P = 0.001). Twenty-five percent of male patients carried the risk allele, compared with 10% of female patients (P = 0.024); however, cytokine skewing was similar in both sexes. CONCLUSION: The autoimmune disease risk allele of PTPN22 is associated with skewing of serum cytokine profiles toward higher IFNalpha activity and lower TNFalpha levels in vivo in patients with SLE. This serum cytokine pattern may be relevant in other autoimmune diseases associated with the PTPN22 risk allele. [ABSTRACT FROM AUTHOR]

OBJECTIVE: A haplotype of the interferon regulatory factor 5 (IRF5) gene has been associated with the risk of developing systemic lupus erythematosus (SLE), and our previous studies have demonstrated that high levels of serum interferon-alpha (IFNalpha) activity are a heritable risk factor for SLE. The aim of this study was to determine whether the IRF5 SLE risk haplotype mediates the risk of SLE by predisposing patients to the development of high levels of serum IFNalpha activity. METHODS: IFNalpha levels in 199 SLE patients of European and Hispanic ancestry were measured with a sensitive functional reporter cell assay. The rs2004640, rs3807306, rs10488631, and rs2280714 single-nucleotide polymorphisms (SNPs) in IRF5 were genotyped in these patients. Haplotypes were categorized as SLE risk, neutral, or protective based on published data. RESULTS: SLE patients with risk/risk and risk/neutral IRF5 genotypes had higher serum IFNalpha activity than did those with protective/protective and neutral/protective genotypes (P = 0.025). This differential effect of IRF5 genotype on serum IFNalpha levels was driven largely by SLE patients who were positive for either anti-RNA binding protein (anti-RBP) or anti-double-stranded DNA (anti-dsDNA) autoantibodies (P = 0.012 for risk/risk or risk/neutral versus protective/protective or neutral/protective). The rs3807306 genotype was independently associated with high serum IFNalpha in this autoantibody group. We found no difference in IFNalpha activity according to IRF5 genotype in patients lacking either type of autoantibody or in patients positive for both classes of autoantibody. CONCLUSION: The IRF5 SLE risk haplotype is associated with higher serum IFNalpha activity in SLE patients, and this effect is most prominent in patients positive for either anti-RBP or anti-dsDNA autoantibodies. This study demonstrates the biologic relevance of the SLE risk haplotype of IRF5 at the protein level. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Interferon-alpha (IFNalpha) levels are elevated in many patients with systemic lupus erythematosus (SLE) and may play a primary role in its pathogenesis. The purpose of this study was to determine whether serum IFNalpha activity in SLE patients and their healthy first-degree relatives is highest in early adulthood, when the incidence of SLE is greatest. METHODS: Serum samples from 315 SLE patients, 359 healthy first-degree relatives, and 141 healthy unrelated donors were measured for IFNalpha activity using a functional reporter cell assay. IFNalpha activity was analyzed in relation to age, and subgroups with high levels of IFNalpha activity were identified within the large data sets using a Mann-Whitney sliding window segmentation algorithm. The significance of each subgrouping was ranked by Kruskal-Wallis testing. RESULTS: Age was inversely correlated with IFNalpha activity in female SLE patients (r = -0.20, P = 0.001) as well as their healthy female first-degree relatives (r = -0.16, P = 0.02). In male patients and their healthy male first-degree relatives, there was no significant overall correlation between age and serum IFNalpha activity. The segmentation algorithm revealed significantly increased IFNalpha activity between the ages of 12 and 22 years in female SLE patients and between the ages of 16 and 29 years in male SLE patients. Both male and female healthy first-degree relatives had significantly decreased IFNalpha activity after the age of 50 years. CONCLUSION: Serum IFNalpha activity is higher in younger individuals in the SLE family cohorts, and this tendency is accentuated in affected individuals. This age-related pattern of IFNalpha activity may contribute to the increased incidence of SLE in early adulthood, and interestingly, males and females had similar age-related patterns of IFNalpha activity. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The type I interferon (IFN) pathway is activated in many patients with systemic lupus erythematosus (SLE), and high serum levels of IFN are associated with anti-SSA/Ro autoantibodies. To investigate the clinical features associated with type I IFN production in vivo, we compared serum IFN activity in individuals with anti-SSA/Ro antibodies who were asymptomatic with that in individuals with clinical manifestations of SLE or Sjögren's syndrome (SS). METHODS: Antibody-positive sera from 84 mothers of children with manifestations of neonatal lupus were studied for type I IFN activity, using a functional reporter cell assay. Maternal health status was characterized as asymptomatic, SS, SLE, pauci-SLE, or pauci-SS, based on a screening questionnaire, telephone interview, and review of medical records. The prefix 'pauci-' indicates symptoms insufficient for a formal classification of the disease. RESULTS: Only 4% of asymptomatic mothers had high serum type I IFN activity, compared with 73% with pauci-SLE (P = 5.7 x 10(-5)), 35% with SLE (P = 0.011), and 32% of patients with SS (P = 0.032). One of the 4 patients with pauci-SS had high levels of IFN. The majority of patients for whom longitudinal data were available had stable type I IFN activity over time, and changes in IFN activity were not clearly accompanied by changes in the clinical diagnosis. CONCLUSION: Patients with SLE, patients with pauci-SLE, and patients with SS are more likely to have high serum IFN activity than asymptomatic individuals with SSA/Ro autoantibodies, suggesting that these autoantibodies are insufficient for activation of the type I IFN pathway, and that disease-specific factors are important for type I IFN generation in vivo. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Recent clinical trials suggest that etanercept is ineffective in controlling Sjögren's syndrome (SS). To address the hypothesis that tumor necrosis factor blockade can result in increased levels of interferon-alpha (IFNalpha) and BAFF, we quantified those mediators in plasma from etanercept- and placebo-treated SS patients. METHODS: We studied plasma samples from 20 patients with SS treated with etanercept (25 mg twice weekly) or placebo in a 12-week, randomized, double-blind clinical trial. In addition, we studied plasma samples from 29 healthy controls. IFNalpha activity was determined by reporter cell assay, and BAFF levels were determined by enzyme-linked immunosorbent assay. RESULTS: Baseline IFNalpha plasma activity and BAFF levels were increased in SS patients compared with healthy controls (mean +/- SD IFNalpha plasma activity score 4.43 +/- 2.60 versus 2.08 +/- 0.91; P < 0.0001) (mean +/- SD BAFF level 0.83 +/- 0.27 ng/ml versus 0.60 +/- 0.15 ng/ml; P = 0.008). A significant increase in IFNalpha activity was detected after 12 weeks of treatment in the etanercept group, but not in the placebo group (P = 0.04 and P = 0.58, respectively). Furthermore, a statistically significant increase in BAFF levels was noted in patients receiving etanercept, but not in those receiving placebo (P = 0.01 and P = 0.56, respectively). In vitro culture of control peripheral blood mononuclear cells with etanercept resulted in a dose-dependent increase in the expression of IFNalpha and the IFNalpha-inducible genes IFN-induced protein with tetratricopeptide repeats 1 and BAFF. CONCLUSION: IFNalpha activity and BAFF levels are elevated in the plasma of patients with SS compared with healthy controls. Etanercept treatment exacerbates IFNalpha and BAFF overexpression, providing a possible explanation for the lack of efficacy of this agent in SS. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor α (TNF-α) inhibitors are used in the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn disease, ankylosing spondylitis, and juvenile idiopathic arthritis. Use of TNF inhibitors is associated with the induction of autoimmunity (systemic lupus erythematosus, vasculitis, psoriasis, and sarcoidosis/sarcoid-like granulomas). We report a case of interstitial granulomatous nephritis in a patient with ankylosing spondylitis after 18 months of treatment with adalimumab. Previously reported cases of sarcoid-like reactions secondary to the use of TNF-α inhibitors involved the liver, lung, lymph nodes, central nervous system, and skin. Granulomatous nephritis after adalimumab treatment has not been described. Close observation of patients undergoing treatment with TNF inhibitors for evolving signs and symptoms of autoimmunity is required. Organ involvement is unpredictable, which makes correct diagnosis and management extremely challenging. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated the IFNK locus in SLE susceptibility. We studied IFNK single nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio = 1.93, P = 2.5 x 10(-4)), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific. IFNK SNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association between IFNK SNPs and SLE and skin phenotypes. The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin. [ABSTRACT FROM AUTHOR]

The PIK3C3 locus was implicated in case-case genome-wide association study of systemic lupus erythematosus (SLE) which we had performed to detect genes associated with autoantibodies and serum interferon-alpha (IFN-alpha). Herein, we examine a PIK3C3 promoter variant (rs3813065/-442 C/T) in an independent multiancestral cohort of 478 SLE cases and 522 controls. rs3813065 C was strongly associated with the simultaneous presence of both anti-Ro and anti-Sm antibodies in African-American patients [OR = 2.24 (1.34-3.73), P = 2.0 x 10(-3)]. This autoantibody profile was associated with higher serum IFN-alpha (P = 7.6 x 10(-6)). In the HapMap Yoruba population, rs3813065 was associated with differential expression of ERAP2 (P = 2.0 x 10(-5)), which encodes an enzyme involved in MHC class I peptide processing. Thus, rs3813065 C is associated with a particular autoantibody profile and altered expression of an MHC peptide processing enzyme, suggesting that this variant modulates serologic autoimmunity in African-American SLE patients. [ABSTRACT FROM AUTHOR]

Objective: Activation of endosomal toll-like receptors (TLRs) is one possible driver of inflammation in idiopathic inflammatory myopathies (IIM). We investigated the potential contribution of TLR7 and TLR8 to IIM pathogenesis., Methods: Activation of TLR7/8 in healthy donor peripheral blood mononuclear cells (PBMCs) by immune complexes from patients with IIM and lupus was tested. Autoantibody profiling of patient IgG samples was performed using a 1581-antigen array. TLR7 and/or TLR8 activation by RNA molecules associated with autoantibodies was assessed. Gene expression in human myoblasts and satellite cells following treatment with supernatants from TLR7/8-activated PBMCs was evaluated by NanoString. C57BL/6 mice were dosed intramuscularly with the TLR7/8 agonist R848 and single-cell RNA-sequencing was performed on the muscle to ascertain the cell types responding to TLR7/8 activation and the downstream effects., Results: Overall, 69 patients with IIM were included with representation of dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM) subsets. Immune complexes from patients with IIM, as well as autoantibody-associated RNAs His-tRNA, Y1, Y4 and U1, activated PBMCs to produce IFN-α and IL-6 via TLR7/8. Several canonical (Ro60, Ro52, HIST1H4A) and novel (IL-36RN) autoreactivities correlated highly with TLR7/8 activation. Supernatants from TLR7/8-activated PBMCs had a negative impact on human myoblasts and satellite cells. Endothelial cells were activated by R848 in mouse muscle in vivo, in addition to immune cells such as monocytes and macrophages., Conclusion: Our results suggest that patients with IIM have autoantibodies in their blood causing TLR7/8 activation, which leads to inflammation in muscles with potential deleterious effects., (This article is protected by copyright. All rights reserved.)

Background: Viral infection outcomes vary widely between individuals, ranging from mild symptoms to severe organ failure and death, and it is clear that host genetic factors play a role in this variability. Type I interferon (IFN) is a critical anti-viral cytokine, and we have previously noted differences in type I IFN levels between world populations., Methods: In this study, we investigate the interrelationship between regional European genetic ancestry, type I IFN levels and severe viral infection outcomes., Results: In cohorts of European ancestry lupus patients living in Europe, we noted higher IFN in the Northwestern populations as compared to Southeastern populations. In an independent cohort of European ancestry lupus patients from the USA with varying proportional regional European genetic admixture, we observed the same Northwest vs. Southeast European ancestry IFN gradient. We developed a model to predict type I IFN level based on regional European ancestry (Area under the curve (AUC) = 0.73, P = 6.1e-6). Examining large databases containing serious viral outcomes data, we found that lower predicted IFN in the corresponding European country was significantly correlated with increased viral infection fatality rate, including Coronavirus Disease 2019 (COVID-19), viral hepatitis and HIV [correlation coefficients: -0.79 (P = 4e-2), -0.94 (P = 6e-3) and -0.96 (P = 8e-2), respectively]., Conclusions: This association between predicted type I IFN level and viral outcome severity suggests a potential causal relationship, as greater intrinsic type I IFN is beneficial in host defense against viruses. Genetic testing could provide insight into individual and population level risk of fatality due to viruses prior to infection, across a wide range of viral pathogens., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Lupus Nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) that affects kidney function. Here, we investigated the role of CD11b, a protein encoded by the ITGAM gene, in the development of LN and its functional activation as a therapeutic strategy. Genetic coding variants of ITGAM significantly increase the risk for SLE and LN by producing a less active CD11b and leading to elevated levels of type I interferon (IFN I). However, a molecular mechanism for how these variants increase LN risk has been unclear. Here, we determined that these variants also significantly associate with elevations in soluble urokinase plasminogen activator receptor (suPAR), a known biomarker linked to kidney disease, suggesting a novel molecular connection. Pharmacologic activation of CD11b with a novel, clinical-stage agonist ONT01 significantly suppressed suPAR production in myeloid cells and reduced systemic inflammation and kidney damage in multiple experimental models of LN. Importantly, delaying treatment with ONT01 until after disease onset also significantly reduced serum suPAR and inflammatory cytokines, and decreased immune complex deposition in the glomerulus, glomerulonephritis and albuminuria, suggesting that CD11b activation is therapeutic for LN. Genetic activation of CD11b via a gain-of-function CD11b mutation also showed complete protection from LN, whereas genetic deletion of CD11b worsened the disease in mice, providing further evidence of the role of CD11b activation in regulating LN. Finally, transfer of human LN PBMCs generated human LN like disease in mice that was significantly reduced by ONT01. Together, these data provide strong evidence that ONT01 mediated CD11b activation can therapeutically modulate TLR7-driven inflammation and protect against LN. These findings support clinical development of CD11b agonists as novel therapeutics for treating lupus nephritis in human patients.

In genomic medicine, the concept of genetically transitional disease (GTD) refers to cases in which gene mutation is necessary but not sufficient to cause disease. In this Perspective, we apply this novel concept to rheumatic diseases, which have been linked to hundreds of genetic variants via association studies. These variants are in the 'grey zone' between monogenic variants with large effect sizes and common susceptibility alleles with small effect sizes. Among genes associated with rare autoinflammatory diseases, many low-frequency and/or low-penetrance variants are known to increase susceptibility to systemic inflammation. In autoimmune diseases, hundreds of HLA and non-HLA genetic variants have been revealed to be modest- to moderate-risk alleles. These diseases can be reclassified as GTDs. The same concept could apply to many other human diseases. GTD could improve the reporting of genetic testing results, diagnostic yields, genetic counselling and selection of therapy, as well as facilitating research using a novel approach to human genetic diseases., (© 2024. Springer Nature Limited.)

Patients with a history of endometriosis have an increased risk of developing various autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis and celiac disease. There is a potential association between endometriosis and an increased susceptibility for Sjögren's syndrome (SS). SS is a common chronic, inflammatory, systemic, autoimmune, multifactorial disease of complex pathology, with genetic, epigenetic and environmental factors contributing to the development of this condition. It occurs in 0.5‑1% of the population, is characterized by the presence of ocular dryness, lymphocytic infiltrations and contributes to neurological, gastrointestinal, vascular and dermatological manifestations. Endometriosis is an inflammatory, estrogen‑dependent, multifactorial, heterogeneous gynecological disease, affecting ≤10% of reproductive‑age women. It is characterized by the occurrence of endometrial tissue outside the uterine cavity, mainly in the pelvic cavity, and is associated with pelvic pain, dysmenorrhea, deep dyspareunia and either subfertility or infertility. It is still unclear whether SS appears as a secondary response to endometriosis, or it is developed due to any potential shared mechanisms of these conditions. The aim of the present review was to explore further the biological basis only of the co‑occurrence of these disorders but not their association at clinical basis, focusing on the analysis of the partially shared genetic background between endometriosis and SS, and the clarification of the possible similarities in the underlying pathogenetic mechanisms and the relevant molecular pathways.

Systemic lupus erythematosus (SLE) is a severe multisystem autoimmune disease that can cause injury in almost every body system. While considered a classic example of autoimmunity, it is still relatively poorly understood. Treatment with immunosuppressive agents is challenging, as many agents are relatively non-specific, and the underlying disease is characterized by unpredictable flares and remissions. This State of The Art Review provides a comprehensive current summary of systemic lupus erythematosus based on recent literature. In basic and translational science, this summary includes the current state of genetics, epigenetics, differences by ancestry, and updates about the molecular and immunological pathogenesis of systemic lupus erythematosus. In clinical science, the summary includes updates in diagnosis and classification, clinical features and subphenotypes, and current guidelines and strategies for treatment. The paper also provides a comprehensive review of the large number of recent clinical trials in systemic lupus erythematosus. Current knowns and unknowns are presented, and potential directions for the future are suggested. Improved knowledge of immunological pathogenesis and the molecular differences that exist between patients should help to personalize treatment, minimize side effects, and achieve better outcomes in this difficult disease., Competing Interests: Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: EFM receives research funding from the National Health and Medical Research Council of Australia, Lupus Research Alliance, AbbVie, Amgen, AstraZeneca, Biogen, BristolMyersSquibb, Eli Lilly, EMD Serono, Genentech, GSK, Janssen, and UCB; and consulting fees from AbbVie, AstraZeneca, Biogen, BristolMyersSquibb, Capella, Eli Lilly, EMD Serono, Genentech, Gilead, Novartis, and Zenas. RFR receives research funding from the Lupus Research Alliance Diversity in Lupus Research Career Development Award. AB receives research funding from the Lupus Research Alliance Diversity in Lupus Research Career Development Award and the National Institutes of Health K23AI163359; and consulting fees from GSK, Novartis, and UCB. TBN receives research funding from EMD Serono, Zenas Biopharma, NIH (AI164968, DK107984, AI167271, AR078416, AR065964), and the Lupus Research Foundation; and consulting fees from AstraZeneca, Progentec, S3 Connected Health, GSK, Thermo Fisher, Roivant Sciences, Ventus, Toran, and Inova., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Type I interferon (IFN-I) is thought to play a role in many systemic autoimmune diseases. IFN-I pathway activation is associated with pathogenic features, including the presence of autoantibodies and clinical phenotypes such as more severe disease with increased disease activity and damage. We will review the role and potential drivers of IFN-I dysregulation in 5 prototypic autoimmune diseases: systemic lupus erythematosus, dermatomyositis, rheumatoid arthritis, primary Sjögren syndrome, and systemic sclerosis. We will also discuss current therapeutic strategies that directly or indirectly target the IFN-I system., (Copyright © 2023 by the Journal of Rheumatology.)

Background: Systemic lupus erythematosus (SLE) is heterogeneous in organ involvement and disease severity, presenting a broad clinical phenotype. Systemic type I interferon (IFN) activity has been shown to be associated with lupus nephritis, autoantibodies, and disease activity in treated SLE patients; however, these relationships are unknown in treatment-naive patients. We aimed to determine the relationship of systemic IFN activity with clinical phenotypes, disease activity, and damage accrual in treatment-naive SLE patients before and after induction and maintenance therapy., Methods: Forty treatment-naive SLE patients were enrolled for this retrospective longitudinal observational study to examine the relationship between serum IFN activity and clinical manifestations of EULAR/ACR-2019 criteria domains, disease activity measures, and damage accrual. As controls, 59 other treatment-naive rheumatic disease patients and 33 healthy individuals were recruited. Serum IFN activity was measured by WISH bioassay and presented as an IFN activity score., Results: Treatment-naive SLE patients had significantly higher serum IFN activity than other rheumatic disease patients (score: 97.6 and 0.0, respectively, p < 0.001). High serum IFN activity was significantly associated with fever, hematologic disorders (leukopenia), and mucocutaneous manifestations (acute cutaneous lupus and oral ulcer) of EULAR/ACR-2019 criteria domains in treatment-naive SLE patients. Serum IFN activity at baseline significantly correlated with SLEDAI-2K scores and decreased along with a decrease in SLEDAI-2K scores after induction and maintenance therapy (R 2 = 0.112, p = 0.034). SLE patients who developed organ damage (SDI ≥ 1) had higher serum IFN activity at baseline than those who did not (SDI = 0) (150.0 versus 57.3, p= 0.018), but the multivariate analysis did not detect its independent significance (p = 0.132)., Conclusions: Serum IFN activity is characteristically high and is linked to fever, hematologic disorders, and mucocutaneous manifestations in treatment-naive SLE patients. Serum IFN activity at baseline correlates with disease activity and decreases in parallel with a decrease in disease activity after induction and maintenance therapy. Our results suggest that IFN plays an important role in the pathophysiology of SLE and that serum IFN activity at baseline may be a potential biomarker for the disease activity in treatment-naive SLE patients., (© 2023. The Author(s).)

Autoimmune diseases vary in the magnitude and diversity of autoantibody profiles, and these differences may be a consequence of different types of breaks in tolerance. Here, we compared the disparate autoimmune diseases autoimmune polyendocrinopathy-candidiasis-ecto-dermal dystrophy (APECED), systemic lupus erythematosus (SLE), and Sjogren's syndrome (SjS) to gain insight into the etiology of breaks in tolerance triggering autoimmunity. APECED was chosen as a prototypical monogenic disease with organ-specific pathology while SjS and SLE represent polygenic autoimmunity with focal or systemic disease. Using protein microarrays for autoantibody profiling, we found that APECED patients develop a focused but highly reactive set of shared mostly anti-cytokine antibodies, while SLE patients develop broad and less expanded autoantibody repertoires against mostly intracellular autoantigens. SjS patients had few autoantibody specificities with the highest shared reactivities observed against Ro-52 and La. RNA-seq B-cell receptor analysis revealed that APECED samples have fewer, but highly expanded, clonotypes compared with SLE samples containing a diverse, but less clonally expanded, B-cell receptor repertoire. Based on these data, we propose a model whereby the presence of autoreactive T-cells in APECED allows T-dependent B-cell responses against autoantigens, while SLE is driven by breaks in peripheral B-cell tolerance and extrafollicular B-cell activation. These results highlight differences in the autoimmunity observed in several monogenic and polygenic disorders and may be generalizable to other autoimmune diseases., Competing Interests: TC, PD, SK, SO, MS, QA, JZ, ET, JV, JD, AB are/have been employees of EMD Serono, Billerica MA, USA or Merck KGaA, Darmstadt, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. The authors declare that this study received funding from EMD Serono Inc and Merck KGaA. The funders were involved in the study design, collection, analysis, interpretation of data, the writing of this article and the decision to submit it for publication., (Copyright © 2023 Clarke, Du, Kumar, Okitsu, Schuette, An, Zhang, Tzvetkov, Jensen, Niewold, Ferre, Nardone, Lionakis, Vlach, DeMartino and Bender.)

Objective: Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE). The pathogenesis is incompletely understood and diagnostic biomarkers are scarce. We investigated interleukin (IL) 16 as a potential biomarker for LN in a well-characterised cohort of patients with SLE., Methods: We measured urinary (u-) and plasma (p-) levels of IL-16 in predefined patient groups using ELISA: LN (n=84), active non-renal SLE (n=63), inactive non-renal SLE (n=73) and matched population controls (n=48). The LN group included patients with recent biopsy-confirmed proliferative (PLN, n=47), mesangioproliferative (MES, n=11) and membranous (MLN, n=26) LN. Renal expression of IL-16 was investigated by immunohistochemistry. Associations between IL-16 measurements and clinical parameters and the diagnostic value for LN were explored., Results: p-IL-16 was detected in all investigated cases and high p-IL-16 levels were observed in patients with active SLE. u-IL-16 was detected (dt-u-IL-16) in 47.6% of patients with LN, while only up to 17.8% had dt-u-IL-16 in other groups. In the LN group, 68% of patients with PLN had dt-u-IL-16, while the proportions in the MLN and MES groups were lower (11.5% and 45.5%, respectively). The highest u-IL-16 levels were detected in the PLN group. In the regression model, u-IL-16 levels differentiated PLN from other LN patient subgroups (area under the curve 0.775-0.896, p<0.0001). dt-u-IL-16 had superior specificity but slightly lower sensitivity than elevated anti-double-stranded DNA and low complement C3 or C4 in diagnosing PLN. A high proportion of LN kidney infiltrating cells expressed IL-16., Conclusions: We demonstrate that detectable u-IL-16 can differentiate patients with PLN from those with less severe LN subtypes and active non-renal SLE. Our findings suggest that u-IL-16 could be used as a screening tool at suspicion of severe LN. Furthermore, the high IL-16 levels in plasma, urine and kidney tissue imply that IL-16 could be explored as a therapeutic target in SLE., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR = 29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in antiviral immunity., (Copyright © 2022. Published by Elsevier Inc.)

Biopsies of inflammatory tissue contain a complex network of interacting cells, orchestrating the immune or autoimmune response. While standard histological examination can identify relationships, it is clear that a great amount of data on each slide is not quantitated or categorized in standard microscopic examinations. To deal with the huge amount of data present in biopsy tissue in an unbiased and comprehensive way, we have developed a deep learning algorithm to identify immune cells in biopsies of inflammatory lesions. We focused on T follicular helper (Tfh) cell subsets and B cells in dermatomyositis biopsy images. We achieved strong performance on detection and classification of cells, including the rare Tfh cell subsets present in the tissue. This algorithm could be used to perform distance mapping between cell types in tissue, and could be easily adapted to other disease states., (Copyright © 2022. Published by Elsevier B.V.)

Objective: Axonal/neuronal damage has been shown to be a pathological finding that precedes neuropsychiatric manifestations in SLE. The objective of this study was to determine the presence of axonal dysfunction in childhood-onset SLE patients (cSLE) and to determine clinical, immunological and treatment features associated with its occurrence., Methods: We included 86 consecutive cSLE patients [median age 17 (range 5-28) years] and 71 controls [median age 18 (5-28) years]. We performed proton magnetic resonance spectroscopic imaging using point resolved spectroscopy sequence over the superior-posterior region of the corpus callosum and signals from N-acetylaspartate (NAA), choline-based (CHO), creatine-containing (Cr), myo-inositol (mI), glutamate, glutamine and lactate were measured and metabolites/Cr ratios were determined. Complete clinical, laboratory and neurological evaluations were performed in all subjects. Serum IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, TNF-α and INF-γ cytokine levels, antiribosomal P protein antibodies (anti-P) and S100β were measured by ELISA using commercial kits. Data were compared by non-parametric tests., Results: NAA/Cr ratios (P = 0.035) and lactate/Cr ratios (P = 0.019) were significantly decreased in cSLE patients when compared with controls. In multivariate analysis, IFN-γ levels [odds ratio (OR) = 4.1; 95% CI: 2.01, 7.9] and depressive symptoms (OR = 1.9; 95% CI: 1.1, 3.2) were associated with NAA/Cr ratio. Increased CHO/Cr was associated with the presence of cognitive impairment (OR = 3.4; 95% CI: 2.034, 5.078; P < 0.001). mI/Cr ratio correlated with cumulative glucocorticoids dosage (r = 0.361, P = 0.014)., Conclusion: NAA and CHO ratios may be useful as biomarkers in neuropsychiatric cSLE. Longitudinal studies are necessary to determine whether they predict structural damage., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Previous studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the effect of IFN in LN., Methods: Two hundred and twenty-one patients with systemic lupus erythematosus were studied. Serum IFN activity was measured by WISH bioassay. mRNA in situ hybridization was used in renal tissue to measure expression of the representative IFN-induced gene, IFN-induced protein with tetratricopeptide repeats-1 ( IFIT1 ), and the plasmacytoid dendritic cell (pDC) marker gene C-type lectin domain family-4 member C ( CLEC4C ). Podocyte cell line gene expression was measured by real-time PCR., Results: Class III/IV LN prevalence was significantly increased in patients with high serum IFN compared with those with low IFN (odds ratio 5.40, P = 0.009). In multivariate regression models, type I IFN was a stronger predictor of class III/IV LN than complement C3 or anti-dsDNA antibody, and could account for the association of these variables with LN. IFIT1 expression was increased in all classes of LN, but most in the glomerular areas of active class III/IV LN kidneys. IFIT1 expression was not closely colocalized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules., Conclusion: Systemic high IFN is involved in the pathogenesis of severe LN. We did not find colocalization of pDCs with IFN signature in renal tissue, and instead observed the greatest intensity of the IFN signature in glomerular areas, which could suggest a blood source of IFN., (Copyright © 2022 by the Journal of Rheumatology.)

Dysregulated IFN-1 responses play crucial roles in the development of multiple forms of autoimmunity. Many patients with lupus, systemic sclerosis, Sjogren's syndrome, and dermatomyositis demonstrate enhanced IFN-1 signaling. IFN-1 excess is associated with disease severity and autoantibodies and could potentially predict response to newer therapies targeting IFN-1 pathways. In this review, we provide an overview of the signaling pathway and immune functions of IFN-1s in health and disease. We also review the systemic autoimmune diseases classically associated with IFN-1 upregulation and current therapeutic strategies targeting the IFN-1 system., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We performed expression quantitative trait locus (eQTL) analysis in single classical (CL) and non-classical (NCL) monocytes from patients with systemic lupus erythematosus (SLE) to quantify the impact of well-established genetic risk alleles on transcription at single-cell resolution., Methods: Single-cell gene expression was quantified using qPCR in purified monocyte subpopulations (CD14 ++ CD16 - CL and CD14 dim CD16 + NCL) from SLE patients. Novel analysis methods were used to control for the within-person correlations observed, and eQTLs were compared between cell types and risk alleles., Results: The SLE-risk alleles demonstrated significantly more eQTLs in NCLs as compared to CLs (p = 0.0004). There were 18 eQTLs exclusive to NCL cells, 5 eQTLs exclusive to CL cells, and only one shared eQTL, supporting large differences in the impact of the risk alleles between these monocyte subsets. The SPP1 and TNFAIP3 loci were associated with the greatest number of transcripts. Patterns of shared influence in which different SNPs impacted the same transcript also differed between monocyte subsets, with greater evidence for synergy in NCL cells. IRF1 expression demonstrated an on/off pattern, in which expression was zero in all of the monocytes studied from some individuals, and this pattern was associated with a number of SLE risk alleles. We observed corroborating evidence of this IRF1 expression pattern in public data sets., Conclusions: We document multiple SLE-risk allele eQTLs in single monocytes which differ greatly between CL and NCL subsets. These data support the importance of the SPP1 and TNFAIP3 risk variants and the IRF1 transcript in SLE patient monocyte function., (© 2021. The Author(s).)

Introduction: Immune checkpoint inhibitors (ICIs) are increasingly used to treat advanced cancer. Rheumatoid arthritis (RA) is associated with an increased risk of malignancies; however, patients with RA have been excluded from ICI trials. In this study, we evaluated risk of toxicity after initiation of ICI treatment in RA patients., Methods: We conducted a single-institution, medical records review analysis to assess the incidence of immune-related adverse events (irAEs) and autoimmune disease (AID) flares among patients with AIDs treated with ICIs from 2011 to 2018. A subgroup analysis for RA patients was performed with frequencies of irAEs and AID flares reported., Results: Twenty-two patients with RA who were treated with ICI for malignancy were identified. At the time of ICI initiation, 86% had inactive RA disease activity. Immune-related adverse events occurred in 7 (32%) of patients, with 2 (9%) developing grade 3 (i.e., severe) irAEs. Immune checkpoint inhibitors were temporarily discontinued because of irAEs in 5 patients (23%), and permanently in 1 patient. Rheumatoid arthritis flares occurred in 12 patients (55%). Of those, 10 (83%) received oral corticosteroids with an adequate treatment response., Conclusions: Our analysis suggests that irAEs following ICI treatment are not increased among RA patients compared with other cancer patients. Heightened RA disease activity during ICI treatment is common, but most adverse events are manageable with oral corticosteroids, and few require permanent ICI discontinuation. A close collaboration between the oncologist and rheumatologist is advisable when considering ICIs in patients with RA., Competing Interests: J.W. consults for and has received less than $10,000 per annum from Merck, Genentech, Astra Zeneca, GSK, Novartis, Nektar, Medivation, Celldex, Incyte, and EMD Serono and $10,000 to $25,000 from BMS for membership on Advisory Boards; holds equity in CytoMx, Biond, and Altor; is on a scientific advisory board for Celldex, CytoMx, Incyte, Biond, Protean, CV6, and Sellas; and was named on a patent from Moffitt Cancer Center on an ipilimumab biomarker and a PD-1 patent from Biodesix. The other authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Peripheral vascular diseases may induce chronic ischemia and cellular injury distal to the arterial obstruction. Cellular senescence involves proliferation arrest in response to stress, which can damage neighboring cells. Renal artery stenosis (RAS) induces stenotic-kidney dysfunction and injury, but whether these arise from cellular senescenceand their temporal pattern remain unknown., Methods: Chronic renal ischemia was induced in transgenic INK-ATTAC and wild type C57BL/6 mice by unilateral RAS, and kidney function ( in vivo micro-MRI) and tissue damage were assessed. Mouse healthy and stenotic kidneys were analyzed using unbiased single-cell RNA-sequencing. To demonstrate translational relevance, cellular senescence was studied in human stenotic kidneys., Results: Using intraperitoneal AP20187 injections starting 1, 2, or 4 weeks after RAS, selective clearance of cells highly expressing p16 Ink4a attenuated cellular senescence and improved stenotic-kidney function; however, starting treatment immediately after RAS induction was unsuccessful. Broader clearance of senescent cells, using the oral senolytic combination dasatinib and quercetin, in C57BL/6 RAS mice was more effective in clearing cells positive for p21 ( Cdkn1a ) and alleviating renal dysfunction and damage. Unbiased, single-cell RNA sequencing in freshly dissociated cells from healthy and stenotic mouse kidneys identified stenotic-kidney epithelial cells undergoing both mesenchymal transition and senescence. As in mice, injured human stenotic kidneys exhibited cellular senescence, suggesting this process is conserved., Conclusions: Maladaptive tubular cell senescence, involving upregulated p16 ( Cdkn2a ), p19 ( Cdkn2d ), and p21 ( Cdkn1a ) expression, is associated with renal dysfunction and injury in chronic ischemia. These findings support development of senolytic strategies to delay chronic ischemic renal injury., (Copyright © 2021 by the American Society of Nephrology.)

T-cell dysregulation has been implicated in the loss of tolerance and overactivation of B cells in systemic lupus erythematosus (SLE). Recent studies have identified T-cell subsets and genetic, epigenetic, and environmental factors that contribute to pathogenic T-cell differentiation, as well as disease pathogenesis and clinical phenotypes in SLE. Many therapeutics targeting T-cell pathways are under development, and although many have not progressed in clinical trials, the recent approval of the calcineurin inhibitor voclosporin is encouraging. Further study of T-cell subsets and biomarkers of T-cell action may pave the way for specific targeting of pathogenic T-cell populations in SLE., Competing Interests: Disclosure statement and funding T.B. Niewold: grants from the Colton Center for Autoimmunity, NIH (AR060861, AR057781, AR065964, AI071651), the Lupus Research Foundation, and the Lupus Research Alliance; T.B. Niewold has received research grants from EMD Serono and Janssen, Inc, and has consulted for Thermo Fisher, Toran, Ventus, Roivant Sciences, and Inova, all unrelated to the current article. R. Fernandez-Ruiz and J.L. Paredes have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

As the world navigates the coronavirus disease 2019 (COVID-19) pandemic, there is a growing need to assess its impact in patients with autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE). Patients with SLE are a unique population when considering the risk of contracting COVID-19 and infection outcomes. The use of systemic glucocorticoids and immunosuppressants, and underlying organ damage from SLE are potential susceptibility factors. Most patients with SLE have evidence of high type I interferon activity, which may theoretically act as an antiviral line of defense or contribute to the development of a deleterious hyperinflammatory response in COVID-19. Other immunopathogenic mechanisms of SLE may overlap with those described in COVID-19, thus, studies in SLE could provide some insight into immune responses occurring in severe cases of the viral infection. We reviewed the literature to date on COVID-19 in patients with SLE and provide an in-depth review of current research in the area, including immune pathway activation, epidemiology, clinical features, outcomes, and the psychosocial impact of the pandemic in those with autoimmune disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Systemic lupus erythematosus (SLE) is a complex and heterogeneous systemic autoimmune disease associated with innate and adaptive immune dysregulation. SLE occurs primarily in females of childbearing age, with increased prevalence and severity in minority populations. Despite improvements in treatment modalities, SLE patients frequently experience periods of heightened disease activity and flare that can lead to permanent organ damage, increased morbidity, and early mortality. Such outcomes impair quality of life and inflict a significant socioeconomic burden. Predicting changes in SLE disease activity could allow for closer monitoring and preemptive treatment, but existing clinical, demographic and serologic markers have been only modestly predictive. Novel, proactive approaches to clinical disease management are thus critically needed. Panels of blood biomarkers can detect a breadth of immune pathway dysregulation that captures SLE heterogeneity and disease activity. Alterations in the balance of pro-inflammatory and regulatory soluble mediators have been associated with changes in clinical disease activity and are detectable several weeks prior to clinical flare occurrence. A soluble mediator score has been highly predictive of impending flare in both European American and African American SLE patients, and this score does not require a priori knowledge of specific pathway activation in the patient. We review current concepts of disease activity and flare in SLE, focusing on the potential of novel blood biomarkers to characterize and predict changes in disease activity. Measuring the disordered immune response in SLE in this way promises to improve disease management and prevent organ damage in SLE., (Copyright © 2021 Progentec Diagnostics, Inc. Published by Elsevier Ltd.. All rights reserved.)