Search

Introduction: Tyrosine kinase 2 (TYK2) mediates signaling of Type I interferons and IL-23, key cytokines involved in systemic lupus erythematosus (SLE) pathogenesis. Deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, is approved in multiple countries for the treatment of adults with plaque psoriasis. This analysis assessed the efficacy and safety of deucravacitinib in patients with active SLE. Methods: This 48-week, double-blind, phase 2 trial (NCT03252587) randomized patients 1:1:1:1 to deucravacitinib (3 mg BID, 6 mg BID, 12 mg QD) or placebo. Oral corticosteroid tapering was required from weeks 8-20; further tapering was optional from weeks 32-40. The primary endpoint was the proportion of patients achieving SLE Responder Index-4 (SRI[4]) at week 32. Key secondary endpoints at week 48 included percentage of patients achieving SRI(4) and decrease of ≥50% from baseline Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI-50), in patients with baseline CLASI ≥10. Change from baseline in CLASI Activity Score (CLASI-A) over time was also assessed. Results: Of 363 randomized patients, 275 (76%) completed 48 weeks of treatment. Baseline demographic and disease characteristics were balanced across treatment groups, with baseline mean CLASI-A scores ranging from 8.0 to 8.6. The primary endpoint at week 32 was met, with significantly greater proportions of patients in deucravacitinib 3 mg BID and 6 mg BID groups vs placebo achieving SRI(4) responses (placebo: 34.4%; deucravacitinib 3 mg BID: 58.2%, P=0.0006; 6 mg BID: 49.5%, P=0.021; 12 mg QD: 44.9%, P=0.078). Patients treated with deucravacitinib demonstrated improvement across all secondary endpoints compared with placebo. In patients with CLASI ≥10 at baseline, greater mean changes from baseline in CLASI-A were observed in deucravacitinib vs placebo over 48 weeks of treatment (placebo: 16.7%; deucravacitinib 3 mg BID: 69.6%, P=0.0006; 6 mg BID: 56.0%, P=0.0058; 12 mg QD: 62.1%, P=0.0009). Rates of adverse events (AEs), serious AEs, and AEs of interest were similar between deucravacitinib and placebo groups. Most common AEs with deucravacitinib were upper respiratory tract infection, nasopharyngitis, headache, and urinary tract infection. No deaths, major adverse cardiac events, thrombotic events, systemic opportunistic infections, or active tuberculosis occurred. Conclusion: Deucravacitinib demonstrated sustained, meaningful clinical efficacy in SRI(4), improvement in mucocutaneous activity as measured by CLASI-A responses, and was well tolerated in patients with active SLE up to 48 weeks.

Infections are a significant cause of morbidity in Systemic Lupus Erythematosus (SLE). Although oral health is considerably compromised in SLE patients, the role of oral pathogens in influencing lupus pathogenesis is not known. In the present study, antibody responses to a periodontogenic, facultative anaerobic bacterium, Aggregatibacter actinomycetemcomitans (Aa), (which serve as an indicator of past or ongoing infection with Aa), were measured in SLE patients (n=587) and healthy controls (n=75). The associations between anti-Aa antibody titers and clinical measures of SLE were evaluated. The effect of Aa infection on development of lupus was investigated in the NZM2328 mice. The ability of Aa to induce neutrophil extracellular traps (NETs) was studied in vitro. Both SLE patients and controls showed the presence of anti-Aa. In SLE patients, the anti-Aa titers correlated strongly with anti-dsDNA, anti-chromatin, anti-RNP, and anti-Sm; but not with anti-Ro52, anti-Ro60, and anti-La antibodies. NZM2328 mice developed a robust immune response to Aa, and the Aa infection caused an accelerated onset of autoantibody and renal disease. In addition, Aa readily induced NETosis in NZM2328 neutrophils. Our data suggest for the first time that SLE patients are exposed to oral pathogen Aa, and this exposure significantly influences immune responses against a subset of lupus-associated autoantigens, possibly through NETosis. Furthermore, our studies suggest that management of oral health in SLE patients might prove to be beneficial for controlling lupus.

SLE is a multifaceted disease characterized by immune dysregulation and varied disease activity. We evaluated changes in plasma soluble mediators (n=52) preceding clinically-defined disease flare, in 13 African American (AA) SLE patients who developed disease flare 6 or 12 weeks after baseline assessment compared to matched SLE patients without impending flare and healthy controls. In addition, mediators within samples preceding SLE disease flare and during a clinically stable period from the same individual were compared in 18 AA SLE patients. Patients with impending flare had significant (q

Antinuclear antibodies (ANA) are detected in up to 25% of the population, yet only 5-8% develop autoimmunity. Immunological differences between ANA+ healthy individuals and SLE patients may give us insight into mechanisms by which ANA+ individuals avoid autoimmunity or transition to SLE. European-American ANA+ individuals (n=31) were matched to ANA- controls and SLE patients. Serum cytokine profiles, lymphocyte subset frequency, and lymphocyte reactivity were analyzed. Numerous pro-inflammatory cytokines including IFNγ, IL-2, IL-5 and TNFα were elevated in the serum of ANA+ healthy individuals compared to ANA- controls; however, SLE patients had even higher cytokine levels compared to ANA+ healthy individuals (p>0.05). Interestingly, Type I IFNs, BLyS, IL-12p40 and SCF were only increased in SLE patients (p

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with striking clinical, immunologic and genetic heterogeneity making development of targeted treatment strategies challenging. Previously, we showed transgenic mice with constitutive expression of the DNA-binding protein ARID3a/Bright in all B lymphocytes spontaneously produced autoantibodies. Therefore, we asked if ARID3a expression differed in SLE versus healthy control B lymphocytes. Of 114 SLE patients, 43% had expanded numbers of ARID3a+ peripheral blood B cells. A longitudinal study revealed that numbers of ARID3a+ B cells fluctuated with time, but were highly associated with increased disease activity. ARID3a expression was not limited to B cell subsets that normally express it, but was also apparent in large numbers of naïve B cells in many SLE patients. Therefore, we hypothesize ARID3a+ naïve B cells are precursors of autoantibody producing B cells. Antibody repertoire analyses of ARID3a+ and ARID3a- naïve B cells are in progress. Together, these findings implicate ARID3a as a potential biomarker for disease activity in SLE.

SLE is a waxing and waning disease characterized by major organ involvement, disease flares and immune dysregulation. Understanding mechanisms and identifying biomarkers of flare would help prevent damage and improve management. Plasma samples were obtained from SLE patients on the day of influenza vaccination (BL) and at 6 and 12 weeks post (FU) in 28 European American SLE patients who exhibited SELENA-SLEDAI defined disease flare at 6 (n=13) or 12 (n=15) weeks post-vaccination. Each SLE patient was matched to a unique SLE patient who did not flare (NF), and to a healthy control (HC). Samples from 13 SLE patients with flare were compared to samples from a non-flare year (self nonflare, SNF). Plasma samples were tested for 52 soluble inflammatory mediators using xMAP technology. SLE patients who exhibited disease flare had significantly (p < 0.01) higher levels of BL pro-inflammatory mediators, including Th1, Th2, and Th17-type cytokines compared to NF/SNF SLE patients and HC. Regulatory cytokines, including IL-10 and TGF-β were increased (p < 0.01) at BL in SLE patients not exhibiting disease flare (NF/SNF) compared to SLE flare and HC. TNFR family members, TNFRI, TNFRII, Fas, FasL, CD40L, were increased at BL in SLE flare patients. Select serum cytokines and chemokines are elevated in patients before SLE disease flare, providing important pathways to dissect for mechanism of flare, therapeutic selection or development.

40% of patients who survive acute episodes of thrombotic thrombocytopenic purpura (TTP) associated with severe ADAMTS13 deficiency will relapse. Risk factors for relapse other than severe ADAMTS13 deficiency are unknown. ADAMTS13 autoantibodies, TTP episodes following infection or type I interferon treatment and reported ensuing systemic lupus erythematosus in some patients suggest immune dysregulation. This study asked whether ADAMTS13-deficient TTP patients in remission have peripheral blood transcriptional markers that associate with relapse history. Peripheral blood from 38 patients with acquired autoimmune ADAMTS13-deficient TTP in remission was examined for autoantibodies, type I interferon activity and global gene expression. A subset of patients (1.4-26.6 year follow-up; median 7.6 years) displayed a peripheral blood type I interferon gene signature that associated with elevated serum type I interferon activity and autoantibodies to RNA-binding proteins but not relapse. A second subset of patients (4.1-26.4 year follow-up; median 11.2 years) exhibited a peripheral blood gene signature composed of ribosomal transcripts that associated with relapse history. Patients who had relapsed also expressed higher natural killer cell, T lymphocyte and HLA transcript levels. The immune transcripts positively correlated with episode number but not with time since last episode. These data link a ribosomal/immune gene signature with relapse in acquired, ADAMTS13-deficient TTP.

Abnormal T cell DNA methylation and type-1 interferon play an important role in the pathogenesis of systemic lupus erythematosus. We performed a genome-wide DNA methylation study in two independent sets of lupus patients and matched healthy controls to characterize the DNA methylome in naïve CD4+ T cells in lupus. DNA methylation was quantified for over 485,000 methylation sites across the genome, and differentially methylated sites between lupus patients and controls were identified and then independently replicated. Gene expression analysis was also performed from the same cells to investigate the relationship between the DNA methylation changes observed and mRNA expression levels. We identified and replicated 86 differentially methylated CG sites between patients and controls in 47 genes. Importantly, we observed significant hypomethylation in interferon-regulated genes in naïve T cells from lupus patients, suggesting epigenetic transcriptional accessibility of these genetic loci. The hypomethylation in interferon-regulated genes was not related to lupus disease activity. Gene expression analysis showed overexpression of these genes in total but not naïve CD4+ T cells from lupus patients. Our data suggest epigenetic “poising” of interferon-regulated genes in lupus naïve CD4+ T cells, argue for a novel pathogenic implication for abnormal T cell DNA methylation in lupus, and suggest a mechanism for type-1 interferon hyper-responsiveness in lupus T cells.