Carli, Linda

Elefante, Elena

Ferro, Francesco

Mosca, Marta

Parma, Alice

Signorini, Viola

Stagnaro, Chiara

Tani, Chiara

Undetermined

Open Access Repository

Results Tofacitinib was well tolerated with no worsening ofSLE disease activity, and no severe AEs, opportunistic infec-tions or liver function abnormalities. A total of 43 AEs(mostly mild respiratory infections) occurred in the treatedgroup compared to 28 AEs in placebo. There was a significantincrease in HDL-C and HDL particle size in tofacitinib-treatedpatients at day 56 (p=0.006) accompanied by significantimprovements in plasma protein lecithin: cholesterol acyltrans-ferase (LCAT) concentration. There were also trends forimprovements in vascular stiffness in the tofacitinib-treatedgroup. The Interferon response genes (type I IFN), the levelsof low- density granulocytes (LDGs) and neutrophil extracellu-lar trap (NET remnants) significantly decreased in the tofaciti-nib treated group who were STAT 4 risk allele positive butnot in the placebo group at day 56, accompanied by signifi-cant changes in pSTAT phosphorylation of different immunecells. Levels of activation and checkpoint markers CD103,CXCR3, ICOS, and PD-1 were significantly decreased on mul-tiple T cell subsets, in tofacitinib treated individuals that lackthe STAT4 risk allele.Conclusions In a short-term trial, tofacitinib was well toleratedin SLE subjects with mild-moderate disease activity. Use oftofacitinib resulted in improvements in lipoprotein profile andHDL function and decreases in the type I IFN and aberrantneutrophil responses characteristic of SLE. Long-term studiesare needed to determine the efficacy of tofacitinib in the vari-ous manifestations of SLE.Funding Source(s): Intramural Research Program of theNational Institute of Arthritis and Musculoskeletal and SkinDiseases of the National Institutes of Health and in part byPfizer Inc.Adverse Events in Subjects on Tofacitinib vs Placebo184 PATIENT PERCEPTION OF SLE BURDEN: THE ROLE OFDISEASE ACTIVITY, COMORBIDITIES AND TREATMENT1Elena Elefante*, 2Chiara Tani, 3Francesco Ferro, 2Chiara Stagnaro, Alice Parma,2Linda Carli, 2Viola Signorini, Marta Mosca. 1University of Siena, Siena, Italy;2Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa,Pisa, Italy; 3University of Pisa10.1136/lupus-2019-lsm.184Background Physician-based assessment of SLE activity anddamage may not be able to capture the real disease impact onpatients life. Objective of our study was to investigate the roleof disease activity, comorbidities and treatment in determiningpatient perception of SLE burden.Methods This is a cross-sectional study that enrolls patientswith a diagnosis of SLE (ACR 1997 criteria). For each patient,demographics, comorbidities, treatment, clinical and laboratorydata were collected. Disease activity was evaluated with theSELENA-SLEDAI score and organ damage with the SLICC/DI.The Lupus Impact Tracker (LIT) questionnaire was used toassess SLE impact. The Spearman test has been used for linearcorrelation between continuous data.Results We included 195 adult SLE patients (97,4% Caucasian,94,4% female, mean age 44,212,8 years, median disease dura-tion 13 years).Median SLEDAI at enrollment was 2 (IQR 0–4) andmedian SLICC/DI was 0 (IQR 0–2). 9,8% of patients had aconcomitant fibromyalgia. The most frequent active diseasemanifestations at baseline were hematological (27/195), articu-lar and cutaneous (24/195 both); 13 patients had active renalinvolvement. 52,8% of the cohort was on steroid therapywith a mean daily dose of 2,84,9 mg of methylprednisolone.46,15% was on immunosuppressive treatment and 77,95% onhydroxychloroquine (HCQ). The median LIT score was 20(IQR 7,5–37,5).Among the LIT items, those with the highest score, sugges-tive of a severe disease impact, were: anxiety, fatigue andpain. We found no significant correlation between SLEDAIand the score of each LIT item.We found that active articular and cutaneous manifestations,but not renal involvement, influence patient subjective percep-tion of SLE impact. In the multivariate analysis, active arthritisshows a significant correlation with LIT items relative to: pain(p=0,02), daily activities and future planning (p<0,01), irre-spective of comorbidities. Fibromyalgia resulted associatedwith a higher score for the item of fatigue (p<0,01).Finally, we found that also ongoing therapy can contributeto determine SLE burden. In the multivariate analysis, wefound a significant correlation between steroid therapy andhigher scores for the items of family responsibilities, futureplanning, discomfort due to physical appearance and drug sideeffects (p<0,01), irrespective of disease activity.Abstract 183 Figure 1 Adverse Events by Organ System. Adverse Events in Subjects on Tofacitinib vs PlaceboAbstractsA140 Lupus Science & Medicine 2019;6(Suppl 1):A1–A227 on June 8, 2020 by guest. Protected by copyright.http://lupus.bmj.com/Lupus Sci Med: first published as 10.1136/lupus-2019-lsm.184 on 1 April 2019. Downloaded from Conclusions Disease activity, fibromyalgia and ongoing therapyall contribute to determine SLE burden. In particular, arthritisand skin disease have a great impact on patient daily living.Moreover, steroid therapy negatively influences patient percep-tion of the disease.Funding Source(s): Founding: INTEGRATE project (EuropeanCommission, 3rd Health Program, Proposal ID 769736)185 BARICITINIB-ASSOCIATED CHANGES IN TYPE IINTERFERON GENE SIGNATURE DURING A 24-WEEKPHASE 2 CLINICAL SLE TRIAL1Thomas Dörner, 2Yoshiya Tanaka, 3Michelle Petri, 4Josef S Smolen, 5Ernst R Dow, 5RichardE Higgs, 5Robert J Benschop, 5Adam Abel, 5Maria E Silk, 5Stephanie de Bono, 5RobertW Hoffman*. 1Charite Universitätsmedizin Berlin and Deutsches Rheuma-Forschungszentrum (DRFZ); 2University of Occupational and Environmental Health, Japan;3Johns Hopkins University School of Medicine; 4Medical University of Vienna; 5Eli Lilly andCompany10.1136/lupus-2019-lsm.185Background In the phase 2 study JAHH (NCT02708095),treatment with baricitinib, an oral selective Janus kinase 1/2inhibitor approved for the treatment of rheumatoid arthritis,resulted in significant improvements in patients with activeSLE receiving standard background therapy compared withplacebo.1 Expression of type I-associated interferon (IFN)responsive genes (IRGs) is elevated in patients with SLE.2 Wedeveloped a robust quantitative assay to measure changes inthe IFN signature, and examined the relationship between theIFN signature and measures of clinical outcome.Methods 314 patients were randomized 1:1:1 to receive pla-cebo, baricitinib 2- or 4 mg once daily for 24 weeks in studyJAHH. Total RNA isolated from whole blood was analyzedusing a multiplex assay panel of 6 IRGs at baseline, andWeeks 2, 12, and 24. The assay was developed and optimizedusing RNA samples from 1760 patients with SLE enrolled inphase 3 trials of tabalumab (an anti-B cell activating factormonoclonal antibody),(2) along with healthy controls. TheIFN signature assay produced a bimodal distribution.Results 70% of patients had an elevated IFN signature at base-line. Baricitinib significantly reduced the IFN signature byWeek 24 compared with placebo (2 mg:20%, 4 mg:24%,p0.05), with decreases observed as early as Week 2. Inpatients who had a high IFN signature at baseline, baricitinib4 mg significantly reduced the IFN signature at Weeks 12 (-24%) and 24 (-23%) compared with placebo (p0.01);decreases were also observed at Weeks 12 and 24 with barici-tinib 2 mg, but the difference from placebo was not statisti-cally significant. Baricitinib 4 mg treatment resulted insignificant clinical improvement in the resolution of arthritisor rash determined by the SLEDAI-2K.1 However, the effectof baricitinib on IFN signature reduction (change from base-line and absolute baseline value) did not correlate with SLE-DAI-2K-defined clinical improvement at Week 12 or 24.Conclusions A dose-dependent decrease in the IFN signaturewas observed in baricitinib-treated patients with SLE. Bariciti-nib treatment resulted in clinical improvement across variousmeasures of SLE disease activity.1 Response was observed withbaricitinib regardless of the change in the IFN gene signature.These data suggest that the clinical improvement observed inbaricitinib-treated patients with SLE may be the result ofbaricitinib-mediated effects on multiple cytokine pathways thatmay include, but are not limited to, IFN signaling. Ongoingstudies using gene arrays are now surveying global immunepathways to better characterize the mechanism of action ofbaricitinib in SLE.Funding Source(s): Eli Lilly and CompanyREFERENCES1. Wallace, D. et.al. DOI:10.1136/annrheumdis-2018-eular.19182. Hoffman,W. et.al. ArthritisRheumatol.2017;69:643–654.186 NRF2 REGULATION OF THE INTERFERON SIGNATURE INLUPUS MACROPHAGES1Shuhong Han, 2Haoyang Zhuang, 3Pui Lee, 4Mingjia Li, 5Peter Nigrovic, 6WestleyH Reeves*. 1Division of Rheumatology and Clinical Immunology, University of Florida;21953; 3Div. of Immunology, Boston Children’s Hospital; 4University of Florida; 5Div. ofImmunology, Boston Children’s Hospital; 6Division of Rheumatology and ClinicalImmunology, University of Florida10.1136/lupus-2019-lsm.186Background Peripheral blood cells from two-thirds of adultlupus patients exhibit a gene expression program (interferonsignature) attributed to the over-production of interferon(IFN) and other type I IFNs (IFN-I). IFN-I may be involvedin the pathogenesis of lupus. Although plasmacytoid dendriticcells produce large amounts of IFN-I, our studies in an exper-imental lupus model suggest that macrophages and/or mono-cytes may play an important role in generating the interferonsignature. This study sought to define how macrophages influ-ence the interferon signature.Methods Proinflammatory and anti-inflammatory (pro-resolv-ing) macrophages were isolated from mice with pristane-induced lupus and were analyzed by RNA-sequencing (RNA-Seq) and quantitative PCR (qPCR). Protein expression in mac-rophage subsets was evaluated by flow cytometry. The role ofnuclear factor erythroid 2 like 2 (Nrf2) activators was exam-ined in vivoResults Transcriptional profiling (RNA-Seq) of CD11b+Ly6G-peritoneal macrophages from mice with experimental lupusunexpectedly indicated a strong interferon signature in proin-flammatory (Ly6ChiCD138-), but not anti-inflammatory (Ly6C-CD138+), macrophages exposed to the same IFN-I concentra-tions. Along with higher IFN-I regulated gene expression, proin-flammatory macrophages expressed lower levels of genesregulated by nuclear factor erythroid 2 like 2 (Nrf2) than anti-inflammatory macrophages. Transcript levels of IFN receptor 1chain (Ifnar1), IFNAR surface staining, and mitochondrial super-oxide all were higher in proinflammatory macrophages. Adminis-tration of the Nrf2 activator CDDO-Im to lupus mice decreasedIFNAR expression, blocked IFN-driven Stat1 phosphorylation,and reduced IFN-regulated gene expression. Thus, the interferonsignature in murine lupus critically depends on Nrf2-regulatedchanges in IFNAR expression in macrophages. Human peripheralblood mononuclear cells exhibited a similar pattern: high IFNARexpression in classical monocytes and lower levels in non-classi-cal monocytes. The data suggest that anti-inflammatory macro-phages/monocytes are insensitive to IFN signaling, potentiallyserving a role in the resolution of inflammation.Conclusions These studies reveal that the relative abundanceof different monocyte/macrophage subsets (proinflammatoryAbstractsLupus Science & Medicine 2019;6(Suppl 1):A1–A227 A141 on June 8, 2020 by guest. Protected by copyright.http://lupus.bmj.com/Lupus Sci Med: first published as 10.1136/lupus-2019-lsm.184 on 1 April 2019. Downloaded from 

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184 Patient perception of SLE burden: the role of disease activity, comorbidities and treatment

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