The MIDORA trial: a phase II, randomised, double-blind, placebo-controlled, mechanistic insight and dosage optimisation study of the efficacy and safety of dazodalibep in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate the safety, efficacy and response duration of four different dosing regimens of dazodalibep (DAZ), a non-antibody biological antagonist of CD40L, in patients with rheumatoid arthritis (RA). METHODS: This double-blind study included adult patients with moderate-to-severe active RA with a positive test for serum rheumatoid factor and/or anticitrullinated protein antibodies, an inadequate response to methotrexate, other conventional disease-modifying antirheumatic drugs or tumour necrosis factor-α inhibitors, and no prior treatment with B-cell depleting agents. Eligible participants were randomised equally to five groups receiving intravenous infusions of DAZ or placebo. The primary endpoint was the change from baseline in the Disease Activity Score-28 with C reactive protein (DAS28-CRP) at day 113. Participants were followed through day 309. RESULTS: The study randomised 78 eligible participants. The change from baseline in DAS28-CRP (least squares means±SE) at day 113 was significantly greater for all DAZ groups (-1.83±0.28 to -1.90±0.27; p<0.05) relative to PBO (-1.06±0.26); significant reductions in DAS28-CRP were also observed for all DAZ groups at day 309. The distribution of adverse events was generally balanced among DAZ and PBO groups (74% and 63%, respectively). There were four serious adverse events deemed by investigators to be unrelated to study medication. CONCLUSIONS: DAZ treatment for all dosage regimens significantly reduced DAS28-CRP at day 113 relative to PBO. The safety data suggest an acceptable safety and tolerability profile. Treatment effects at day 113 and the prolonged duration of responses after DAZ cessation support the use of longer dosing intervals. TRIAL REGISTRATION NUMBER: NCT04163991.

Urinary markers differentially associate with kidney inflammatory activity and chronicity measures in patients with lupus nephritis.

OBJECTIVE: Lupus nephritis (LN) is diagnosed by biopsy, but longitudinal monitoring assessment methods are needed. Here, in this preliminary and hypothesis-generating study, we evaluate the potential for using urine proteomics as a non-invasive method to monitor disease activity and damage. Urinary biomarkers were identified and used to develop two novel algorithms that were used to predict LN activity and chronicity. METHODS: Baseline urine samples were collected for four cohorts (healthy donors (HDs, n=18), LN (n=42), SLE (n=17) or non-LN kidney disease biopsy control (n=9)), and over 1 year for patients with LN (n=42). Baseline kidney biopsies were available for the LN (n=46) and biopsy control groups (n=9). High-throughput proteomics platforms were used to identify urinary analytes ≥1.5 SD from HD means, which were subjected to stepwise, univariate and multivariate logistic regression modelling to develop predictive algorithms for National Institutes of Health Activity Index (NIH-AI)/National Institutes of Health Chronicity Index (NIH-CI) scores. Kidney biopsies were analysed for macrophage and neutrophil markers using immunohistochemistry (IHC). RESULTS: In total, 112 urine analytes were identified from LN, SLE and biopsy control patients as both quantifiable and overexpressed compared with HDs. Regression analysis identified proteins associated with the NIH-AI (n=30) and NIH-CI (n=26), with four analytes common to both groups, demonstrating a difference in the mechanisms associated with NIH-AI and NIH-CI. Pathway analysis of the NIH-AI and NIH-CI analytes identified granulocyte-associated and macrophage-associated pathways, and the presence of these cells was confirmed by IHC in kidney biopsies. Four markers each for the NIH-AI and NIH-CI were identified and used in the predictive algorithms. The NIH-AI algorithm sensitivity and specificity were both 93% with a false-positive rate (FPR) of 7%. The NIH-CI algorithm sensitivity was 88%, specificity 96% and FPR 4%. The accuracy for both models was 93%. CONCLUSIONS: Longitudinal predictions suggested that patients with baseline NIH-AI scores of ≥8 were most sensitive to improvement over 6-12 months. Viable approaches such as this may enable the use of urine samples to monitor LN over time.

circMTND5 Participates in Renal Mitochondrial Injury and Fibrosis by Sponging MIR6812 in Lupus Nephritis.

Recent studies have focused on nuclear-encoded circular RNAs (circRNAs) in kidney diseases, but little is known about mitochondrial circRNAs. Differentially expressed circRNAs were analyzed by RNA deep sequencing from lupus nephritis (LN) biopsies and normal human kidneys. In LN renal biopsies, the most downregulated circRNA was circMTND5, which is encoded in the mitochondrial genome. We quantitated circMTND5 by qPCR and localized by fluorescence in situ hybridization (FISH). Mitochondrial abnormalities were identified by electron microscopy. The expression of mitochondrial genes was decreased, and the expression of profibrotic genes was increased on qPCR and immunostaining. RNA binding sites for MIR6812 and circMTND5 were predicted. MIR6812 expression was increased by FISH and qPCR. In HK-2 cells and its mitochondrial fraction, the role of circMTND5 sponging MIR6812 was assessed by their colocalization in mitochondria on FISH, RNA immunoprecipitation, and RNA pulldown coupled with luciferase reporter assay. circMTND5 knockdown upregulated MIR6812, decreased mitochondrial functional gene expression, and increased profibrotic gene expression. Overexpression of circMTND5 reversed these effects in hTGF-ß stimulated HK-2 cells. Similar effects were observed in HK-2 cells with overexpression and with knockdown of MIR6812. We conclude that circMTND5 alleviates renal mitochondrial injury and kidney fibrosis by sponging MIR6812 in LN.

Long-term follow-up after lymphodepleting autologous haematopoietic cell transplantation for treatment-resistant systemic lupus erythematosus.

OBJECTIVE: Autologous haematopoietic cell transplantation (AHSCT) improves immunologic dysfunction in patients with SLE. However, the curative potential of this therapy remains uncertain. This study reports outcomes in SLE patients receiving a lymphodepleting, reduced intensity regimen for AHSCT in SLE. METHODS: Eight patients with SLE refractory to treatment, including i.v. cyclophosphamide (CYC), were enrolled. Five had LN and three CNS involvement as primary indications for transplant. Haematopoietic cell mobilization with CYC, G-CSF and rituximab was followed by collection of CD34+ positively selected cells. The conditioning regimen consisted of concurrent administration of CYC, fludarabine and rituximab. All immunosuppressive medications were discontinued at the start of mobilization and CS were rapidly tapered after the transplant. RESULTS: Five of eight patients achieved a complete response, including a decline in the SLEDAI to zero, which was sustained in four patients for a median of 165 months (range 138-191). One patient achieved a partial response, which was followed by relapse at month 18. Two patients with nephritis and underlying comorbidities in most organs had early deaths from infection and multiorgan failure. AHSCT resulted in profound lymphodepletion, followed by expansion of Treg cells and repopulation of naive T and B cells. Patients with a complete response showed a sustained suppression of the SLE-associated IFN-induced gene signature, marked depletion of memory and plasmablast B cells and resultant sustained elimination of anti-dsDNA antibody. CONCLUSION: Durable clinical and serologic remissions with suppression in the IFN gene signature can be achieved in refractory SLE following lymphodepleting AHSCT. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00076752.

Depleting plasmacytoid dendritic cells reduces local type I interferon responses and disease activity in patients with cutaneous lupus.

Plasmacytoid dendritic cells (pDCs) not only are specialized in their capacity to secrete large amounts of type I interferon (IFN) but also serve to enable both innate and adaptive immune responses through expression of additional proinflammatory cytokines, chemokines, and costimulatory molecules. Persistent activation of pDCs has been demonstrated in a number of autoimmune diseases. To evaluate the potential benefit of depleting pDCs in autoimmunity, a monoclonal antibody targeting the pDC-specific marker immunoglobulin-like transcript 7 was generated. This antibody, known as VIB7734, which was engineered for enhanced effector function, mediated rapid and potent depletion of pDCs through antibody-dependent cellular cytotoxicity. In cynomolgus monkeys, treatment with VIB7734 reduced pDCs in blood below the lower limit of normal by day 1 after the first dose. In two phase 1 studies in patients with autoimmune diseases, VIB7734 demonstrated an acceptable safety profile, comparable to that of placebo. In individuals with cutaneous lupus, VIB7734 profoundly reduced both circulating and tissue-resident pDCs, with a 97.6% median reduction in skin pDCs at study day 85 in VIB7734-treated participants. Reductions in pDCs in the skin correlated with a decrease in local type I IFN activity as well as improvements in clinical disease activity. Biomarker analysis suggests that responsiveness to pDC depletion therapy may be greater among individuals with high baseline type I IFN activity, supporting a central role for pDCs in type I IFN production in autoimmunity and further development of VIB7734 in IFN-associated diseases.

Modulation of Cardiometabolic Disease Markers by Type I Interferon Inhibition in Systemic Lupus Erythematosus.

OBJECTIVE: Neutrophil dysregulation and the type I interferon (IFN) axis have been proposed to contribute to premature cardiovascular disease, a leading cause of mortality in patients with systemic lupus erythematosus (SLE). In the present study, we evaluated the ability of anifrolumab, a type I IFN receptor-blocking antibody, to reduce neutrophil extracellular trap (NET) formation and modulate cardiometabolic disease markers in comparison to placebo. METHODS: Study subjects comprised patients with moderate-to-severe SLE who were enrolled in phase IIb of the MUSE trial (A Phase II, Randomized Study to Evaluate the Efficacy and Safety of MEDI-546 in Subjects with Systemic Lupus Erythematosus), with healthy individuals as controls. Blood samples were collected from SLE patients (n = 305) and healthy controls (n = 10-20) before the initiation of treatment (baseline) and from SLE patients after they had been treated with 300 mg of anifrolumab (n = 99) or placebo (n = 102). Baseline IFN gene signature test status was determined, and the IFN gene signature (21-gene panel) was monitored over time. Serum proteins were measured by multiplex immunoassay or ultrasensitive Simoa assay. NET complexes, cholesterol efflux capacity (CEC), and glycoprotein acetylation (GlycA) and other lipid parameters were assessed in plasma. RESULTS: Formation of NET complexes and levels of tumor necrosis factor (TNF) and interleukin-10 (IL-10) were correlated with extent of type I IFN pathway activity. NET complexes and IL-10 levels were up-regulated in SLE patients compared to healthy controls (P < 0.008). The cardiometabolic disease markers CEC and GlycA were also found to be dysregulated in patients with SLE (P < 0.001 versus healthy controls). Type I IFN receptor inhibition with anifrolumab significantly reduced NET complexes and GlycA and improved CEC compared to baseline (P < 0.05) whereas no improvements were seen with placebo. Levels of TNF and IL-10 were reduced with anifrolumab compared to placebo (P < 0.05). CONCLUSION: These data support a key role for type I IFNs in modulating factors contributing to SLE vasculopathy and suggest that inhibition of this pathway could decrease cardiovascular risk in individuals with SLE.

LNA-anti-miR-150 ameliorated kidney injury of lupus nephritis by inhibiting renal fibrosis and macrophage infiltration.

BACKGROUND: The prevalence of lupus nephritis (LN) remains high despite various emerging monoclonal antibodies against with targeting systemic lupus erythematosus (SLE). Renal fibrosis is the main feature of late stage LN, and novel therapeutic agents are still needed. We previously reported that microRNA (miR)-150 increases in renal biopsies of American LN patients and that miR-150 agonist promotes fibrosis in cultured kidney cells. Presently, we aim to verify whether locked nucleic acid (LNA)-anti-miR-150 can ameliorate LN in mice and to investigate its corresponding mechanisms. METHODS: We first observed natural history and renal miR-150 expression in female Fcgr2b-/- mice of a spontaneously developed LN model. We then verified miR-150 renal absorption and determined the dose of the suppressed miR-150 by subcutaneous injection of LNA-anti-miR-150 (2 and 4 mg/kg). Thirdly, we investigated the therapeutic effects of LNA-anti-miR-150 (2 mg/kg for 8 weeks) on LN mice and the corresponding mechanisms by studying fibrosis-related genes, cytokines, and kidney resident macrophages. Lastly, we detected the expression of renal miR-150 and the mechanism-associated factors in renal biopsies from new onset untreated LN patients. RESULTS: Fcgr2b-/- mice developed SLE indicated by positive serum autoantibodies at age 19 weeks and LN demonstrated by proteinuria at age 32 weeks. Renal miR-150 was overexpressed in LN mice compared to wild type mice. FAM-labeled LNA-anti-miR-150 was absorbed by both glomeruli and renal tubules. LNA-anti-miR-150 suppressed the elevated renal miR-150 levels in LN mice compared to the scrambled LNA without systemic toxicity. Meanwhile, serum double strand-DNA antibody, proteinuria, and kidney injury were ameliorated. Importantly, the elevated renal pro-fibrotic genes (transforming growth factor-ß1, α-smooth muscle antibody, and fibronectin) and decreased anti-fibrotic gene suppressor of cytokine signal 1 were both reversed. Renal pro-inflammatory cytokines (interferon-γ, interleukin-6, and tumor necrosis factor-α) and macrophages were also decreased. In addition, the changes of renal miR-150 and associated proteins shown in LN mice were also seen in human subjects. CONCLUSIONS: LNA-anti-miR-150 may be a promising novel therapeutic agent for LN in addition to the current emerging monoclonal antibodies, and its renal protective mechanism may be mediated by anti-fibrosis and anti-inflammation as well as reduction of the infiltrated kidney resident macrophages.

Anifrolumab effects on rash and arthritis: impact of the type I interferon gene signature in the phase IIb MUSE study in patients with systemic lupus erythematosus.

OBJECTIVE: This post hoc analysis compared anifrolumab 300 mg every 4 weeks with placebo on rash and arthritis measures with different stringency in patients with moderate to severe SLE (phase IIb; MUSE; NCT01438489). Subgroups were analysed by type I interferon gene signature (IFNGS test-high or test-low). METHODS: Rash was measured with the SLE Disease Activity Index 2000 (SLEDAI-2K), British Isles Lupus Assessment Group (BILAG) Index and modified Cutaneous Lupus Erythematosus Disease Area and Severity Index (mCLASI). Arthritis was evaluated using SLEDAI-2K, BILAG and swollen and tender joint counts. Outcomes were measured at week 52. RESULTS: More anifrolumab-treated patients demonstrated resolution of rash by SLEDAI-2K versus placebo: 39/88 (44.3%) versus 13/88 (14.8%), OR (90% CI) 4.56 (2.48 to 8.39), p<0.001; improvement of BILAG: 48/82 (58.5%) versus 24/85 (28.2%), OR (90% CI) 3.59 (2.08 to 6.19), p<0.001; and ≥50% improvement by mCLASI: 57/92 (62.0%) versus 30/89 (33.7%), OR (90% CI) 3.31 (1.97 to 5.55), p<0.001. More anifrolumab-treated patients had improved arthritis by SLEDAI-2K versus placebo: 55/97 (56.7%) versus 42/99 (42.4%), OR (90% CI) 1.88 (1.16 to 3.04), p=0.032; and BILAG: 65/94 (69.1%) versus 47/95 (49.5%), OR (90% CI) 2.47 (1.48 to 4.12), p=0.003; and mean (SD) swollen and tender joint reductions: -5.5 (6.3) versus -3.4 (5.9), p=0.004. Comparable results were demonstrated in IFNGS test-high patients (n=151). In IFNGS test-low patients (n=50), substantial numerical differences in partial rash and arthritis responses were observed in anifrolumab-treated patients versus placebo, with statistical significance only for rash by BILAG in this small population. CONCLUSIONS: Anifrolumab treatment was associated with improvements versus placebo in specific SLE features of arthritis and rash using measures of different stringency. Although driven by robust data in the prevalent IFNGS test-high population, further evaluation in IFNGS test-low patients is warranted.

Type I interferon receptor blockade with anifrolumab corrects innate and adaptive immune perturbations of SLE.

OBJECTIVE: Anifrolumab is a fully human immunoglobulin G1 κ monoclonal antibody specific for subunit 1 of the type I interferon (IFN) α receptor. In a phase IIb study of adults with moderate to severe SLE, anifrolumab treatment demonstrated substantial reductions in multiple clinical endpoints. Here, we evaluated serum proteins and immune cells associated with SLE pathogenesis, type I interferon gene signature (IFNGS) test status and disease activity, and how anifrolumab affected these components. METHODS: Whole blood samples were collected from patients enrolled in MUSE (NCT01438489) for serum protein and cellular assessments at baseline and subsequent time points. Data were parsed by IFNGS test status (high/low) and disease activity. Protein expression and immune cell subsets were measured using multiplex immunoassay and flow cytometry, respectively. Blood samples from healthy donors were analysed for comparison. RESULTS: Baseline protein expression differed between patients with SLE and healthy donors, IFNGS test-high and -low patients, and patients with moderate and severe disease. Anifrolumab treatment lowered concentrations of IFN-induced chemokines associated with B, T and other immune cell migration in addition to proteins associated with endothelial activation that were dysregulated at baseline. IFNGS test-high patients and those with high disease activity were characterised by low baseline numbers of lymphocytes, circulating memory T-cell subsets and neutrophils. Anifrolumab treatment reversed lymphopenia and neutropenia in the total population, and normalised multiple T-cell subset counts in IFNGS test-high patients compared with placebo. CONCLUSIONS: Anifrolumab treatment reversed IFN-associated changes at the protein and cellular level, indicating multiple modes of activity. TRIAL REGISTRATION NUMBER: NCT01438489.

Lupus Low Disease Activity State (LLDAS) attainment discriminates responders in a systemic lupus erythematosus trial: post-hoc analysis of the Phase IIb MUSE trial of anifrolumab.

OBJECTIVES: In a post-hoc analysis, we aimed to validate the Lupus Low Disease Activity State (LLDAS) definition as an endpoint in an systemic lupus erythematosus (SLE) Phase IIb randomised controlled trial (RCT) (MUSE [NCT01438489]) and then utilize LLDAS to discriminate between anifrolumab and placebo. METHODS: Patients received intravenous placebo (n=102) or anifrolumab (300 mg, n=99; 1,000 mg, n=104) Q4W plus standard of care for 48 weeks. LLDAS attainment (SLE Disease Activity Index 2000 ≤4 without major organ activity, no new disease activity, Physician's Global Assessment ≤1, prednisolone ≤7.5 mg/d and standard immunosuppressant dosage tolerance) was assessed. Associations with endpoints and LLDAS attainment differences between treatments were explored. RESULTS: LLDAS attainment at Week 52 was associated with SLE Responder Index 4 (SRI[4]) and British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) (74/85[87%] and 62/84[74%] were also SRI[4] and BICLA responders, respectively; both nominal p<0.001). Only 74/159 (47%) of SRI(4) and 62/121 (51%) of BICLA responders reached LLDAS.Anifrolumab-treated patients achieved earlier LLDAS, and more spent at least half their observed time in LLDAS (OR vs. placebo; 300 mg: 3.04, 95% CI 1.34 to 6.92, nominal p=0.008; 1,000 mg: 2.17, 95% CI 0.93 to 5.03, nominal p=0.072) vs placebo-treated patients. At Week 52, 17/102 (17%), 39/99 (39%) and 29/104 (28%) of patients on placebo, anifrolumab 300 and 1,000 mg, respectively, attained LLDAS (OR vs. placebo; 300 mg: 3.41, 95% CI 1.73 to 6.76, p<0.001; 1,000 mg: 2.03, 95% CI 1.01 to 4.07, nominal p=0.046). CONCLUSIONS: LLDAS attainment represents a clinically meaningful SLE outcome measure, and anifrolumab is associated with more patients who met LLDAS criteria versus placebo. These data support LLDAS as an SLE RCT endpoint. TRIAL REGISTRATION NUMBER: NCT1438489; Post-results.

Anifrolumab, an Anti-Interferon-α Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus.

OBJECTIVE: To assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double-blind, placebo-controlled study of adults with moderate-to-severe systemic lupus erythematosus (SLE). METHODS: Patients (n = 305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks. Randomization was stratified by SLE Disease Activity Index 2000 score (<10 or ≥10), oral corticosteroid dosage (<10 or ≥10 mg/day), and type I IFN gene signature test status (high or low) based on a 4-gene expression assay. The primary end point was the percentage of patients achieving an SLE Responder Index (SRI[4]) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than or equal to the dose at week 1 from week 12 through 24). Other end points (including SRI[4], British Isles Lupus Assessment Group [BILAG]-based Composite Lupus Assessment [BICLA], modified SRI[6], and major clinical response) were assessed at week 52. The primary end point was analyzed in the modified intent-to-treat (ITT) population and type I IFN-high subpopulation. The study result was considered positive if the primary end point was met in either of the 2 study populations. The Type I error rate was controlled at 0.10 (2-sided), within each of the 2 study populations for the primary end point analysis. RESULTS: The primary end point was met by more patients treated with anifrolumab (34.3% of 99 for 300 mg and 28.8% of 104 for 1,000 mg) than placebo (17.6% of 102) (P = 0.014 for 300 mg and P = 0.063 for 1,000 mg, versus placebo), with greater effect size in patients with a high IFN signature at baseline (13.2% in placebo-treated patients versus 36.0% [P = 0.004] and 28.2% [P = 0.029]) in patients treated with anifrolumab 300 mg and 1,000 mg, respectively. At week 52, patients treated with anifrolumab achieved greater responses in SRI(4) (40.2% versus 62.6% [P < 0.001] and 53.8% [P = 0.043] with placebo, anifrolumab 300 mg, and anifrolumab 1,000 mg, respectively), BICLA (25.7% versus 53.5% [P < 0.001] and 41.2% [P = 0.018], respectively), modified SRI(6) (28.4% versus 49.5% [P = 0.002] and 44.7% [P = 0.015], respectively), major clinical response (BILAG 2004 C or better in all organ domains from week 24 through week 52) (6.9% versus 19.2% [P = 0.012] and 17.3% [P = 0.025], respectively), and several other global and organ-specific end points. Herpes zoster was more frequent in the anifrolumab-treated patients (2.0% with placebo treatment versus 5.1% and 9.5% with anifrolumab 300 mg and 1,000 mg, respectively), as were cases reported as influenza (2.0% versus 6.1% and 7.6%, respectively), in the anifrolumab treatment groups. Incidence of serious adverse events was similar between groups (18.8% versus 16.2% and 17.1%, respectively). CONCLUSION: Anifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate-to-severe SLE.

Targeting the Ca(2+) Sensor STIM1 by Exosomal Transfer of Ebv-miR-BART13-3p is Associated with Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease that is associated with inflammation and dysfunction of salivary and lacrimal glands. The molecular mechanism(s) underlying this exocrinopathy is not known, although the syndrome has been associated with viruses, such as the Epstein Barr Virus (EBV). We report herein that an EBV-specific microRNA (ebv-miR-BART13-3p) is significantly elevated in salivary glands (SGs) of pSS patients and we show that it targets stromal interacting molecule 1 (STIM1), a primary regulator of the store-operated Ca(2+) entry (SOCE) pathway that is essential for SG function, leading to loss of SOCE and Ca(2+)-dependent activation of NFAT. Although EBV typically infects B cells and not salivary epithelial cells, ebv-miR-BART13-3p is present in both cell types in pSS SGs. Importantly, we further demonstrate that ebv-miR-BART13-3p can be transferred from B cells to salivary epithelial cells through exosomes and it recapitulates its functional effects on calcium signaling in a model system.

Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study.

OBJECTIVES: The efficacy and safety of sifalimumab were assessed in a phase IIb, randomised, double-blind, placebo-controlled study (NCT01283139) of adults with moderate to severe active systemic lupus erythematosus (SLE). METHODS: 431 patients were randomised and received monthly intravenous sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. Patients were stratified by disease activity, interferon gene-signature test (high vs low based on the expression of four genes) and geographical region. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52. RESULTS: Compared with placebo, a greater percentage of patients who received sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other improvements were seen in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physician's Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (1200 mg monthly), 4-point reductions in the SLE Disease Activity Index-2000 score and reductions in counts of swollen joints and tender joints. Serious adverse events occurred in 17.6% of patients on placebo and 18.3% of patients on sifalimumab. Herpes zoster infections were more frequent with sifalimumab treatment. CONCLUSIONS: Sifalimumab is a promising treatment for adults with SLE. Improvement was consistent across various clinical end points, including global and organ-specific measures of disease activity. TRIAL REGISTRATION NUMBER: NCT01283139; Results.

X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome.

OBJECTIVE: More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in ∼1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. METHODS: All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. RESULTS: We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients. CONCLUSION: The estimated prevalence of SLE and SS in women with 47,XXX was ∼2.5 and ∼2.9 times higher, respectively, than that in women with 46,XX and ∼25 and ∼41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.

EULAR Sjögren's syndrome disease activity index (ESSDAI): a user guide.

The EULAR Sjögren's syndrome (SS) disease activity index (ESSDAI) is a systemic disease activity index that was designed to measure disease activity in patients with primary SS. With the growing use of the ESSDAI, some domains appear to be more challenging to rate than others. The ESSDAI is now in use as a gold standard to measure disease activity in clinical studies, and as an outcome measure, even a primary outcome measure, in current randomised clinical trials. Therefore, ensuring an accurate and reproducible rating of each domain, by providing a more detailed definition of each domain, has emerged as an urgent need. The purpose of the present article is to provide a user guide for the ESSDAI. This guide provides definitions and precisions on the rating of each domain. It also includes some minor improvement of the score to integrate advance in knowledge of disease manifestations. This user guide may help clinicians to use the ESSDAI, and increase the reliability of rating and consequently of the ability to detect true changes over time. This better appraisal of ESSDAI items, along with the recent definition of disease activity levels and minimal clinically important change, will improve the assessment of patients with primary SS and facilitate the demonstration of effectiveness of treatment for patients with primary SS.

Elevated interleukin-10: a new cause of dyslipidemia leading to severe HDL deficiency.

BACKGROUND: Low high-density lipoprotein cholesterol (HDL-C) is a risk factor for coronary artery disease. Investigating mechanisms underlying acquired severe HDL deficiency in noncritically ill patients ("disappearing HDL syndrome") could provide new insights into HDL metabolism. OBJECTIVE: To determine the cause of low HDL-C in patients with severe acquired HDL deficiency. METHODS AND RESULTS: Patients with intravascular large B-cell lymphoma (n = 2), diffuse large B-cell lymphoma (n = 1), and autoimmune lymphoproliferative syndrome (n = 1) presenting with markedly decreased HDL-C, low low-density lipoprotein cholesterol (LDL-C), and elevated triglycerides were identified. The abnormal lipoprotein profile returned to normal after therapy in all 4 patients. All patients were found to have markedly elevated serum interleukin-10 (IL-10) levels that also normalized after therapy. In a cohort of autoimmune lymphoproliferative syndrome patients (n = 93), IL-10 showed a strong inverse correlation with HDL-C (R(2) = 0.3720, P < .0001). A direct causal role for increased serum IL-10 in inducing the observed changes in lipoproteins was established in a randomized, placebo-controlled clinical trial of recombinant human IL-10 in psoriatic arthritis patients (n = 18). Within a week of initiating subcutaneous recombinant human IL-10 injections, HDL-C precipitously decreased to near-undetectable levels. LDL-C also decreased by more than 50% (P < .0001) and triglycerides increased by approximately 2-fold (P < .005). All values returned to baseline after discontinuing IL-10 therapy. CONCLUSION: Increased IL-10 causes severe HDL-C deficiency, low LDL-C, and elevated triglycerides. IL-10 is thus a potent modulator of lipoprotein levels, a potential new biomarker for B-cell disorders, and a novel cause of disappearing HDL syndrome.

Predominant Glandular Cholinergic Dysautonomia in Patients With Primary Sjögren's Syndrome.

OBJECTIVE: The autonomic nervous system (ANS) modulates exocrine gland function. Available data show poor correlation between the degree of function and destruction of the exocrine glands in primary Sjögren's syndrome (SS), suggesting that other mechanisms, such as autonomic dysfunction, may be important in these patients. The aim of this study was to perform a comprehensive analysis of sympathoneural and sympathetic cholinergic function in well-characterized patients with primary SS. METHODS: Twenty-one patients with primary SS (mean ± SEM age 44.2 ± 2.8 years) and 13 healthy control subjects (mean ± SEM age 50.8 ± 1.9 years) were assessed during orthostasis and intravenous injection of edrophonium (10 mg). The postganglionic sympathetic cholinergic system was evaluated by assessing sweat production by means of the Quantitative Sudomotor Axon Reflex Test (QSART). Tests of gastric emptying were used to assess the gastrointestinal ANS in primary SS patients. RESULTS: The velocity index and the acceleration index were significantly higher (P < 0.05) in patients with primary SS as compared to controls, both before and during the orthostatic and edrophonium tests. Findings of other hemodynamic and neurochemical parameters did not differ between primary SS patients and controls during the orthostasis and edrophonium test; however, the edrophonium-induced saliva increment was lower in primary SS patients (P = 0.002). Abnormally low sweat production was found in 4 primary SS patients but in none of the controls, as determined by the QSART. Gastric empting was delayed in 53% of primary SS patients. CONCLUSION: We observed subtle differences in several ANS domains, including the gastrointestinal and sympathocholinergic systems, suggesting the presence of a complex ANS dysfunction in primary SS. The impact was greatest on the exocrine glands, with subtle differences in the cardiac parasympathetic function that were independent of glandular inflammation and atrophy, suggesting an alternative mechanism of disease pathogenesis in primary SS.

The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.

Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.