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      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

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          Abstract

          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.

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          Most cited references28

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          Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.

          Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression "signature" served as a marker for more severe disease involving the kidneys, hematopoetic cells, and/or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.
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            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.
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              Type I IFNs and TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation

              Cross-regulation of Toll-like receptor responses by cytokines is essential for effective host defense, avoidance of toxicity, and homeostasis, but the underlying mechanisms are not well understood. A comprehensive epigenomic approach in human macrophages showed that the proinflammatory cytokines TNF and type I IFNs induce transcriptional cascades that alter chromatin states to broadly reprogram TLR4-induced responses. TNF tolerized inflammatory genes to prevent toxicity, while preserving antiviral and metabolic gene induction. Type I IFNs potentiated TNF inflammatory function by priming chromatin to prevent silencing of inflammatory NF-κB target genes. Priming of chromatin enabled robust transcriptional responses to weak upstream signals. Similar chromatin regulation occurred in human diseases. Our findings reveal that signaling crosstalk between IFNs and TNF is integrated at the level of chromatin to reprogram inflammatory responses, and identify new functions and mechanisms of action of these cytokines.
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                Author and article information

                Journal
                Lupus Sci Med
                Lupus Sci Med
                lupusscimed
                lupus
                Lupus Science & Medicine
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2053-8790
                2018
                26 November 2018
                : 5
                : 1
                : e000284
                Affiliations
                [1 ] departmentArthritis & Clinical Immunology Program , Oklahoma Medical Research Foundation , Oklahoma City, Oklahoma, USA
                [2 ] departmentDivision of Rheumatology, Department of Medicine , Zucker School of Medicine at Hofstra/Northwell, Northwell Health , Great Neck, New York, USA
                [3 ] departmentDepartment of Dermatology , University of Pennsylvania , Philadelphia, Pennsylvania, USA
                [4 ] Corporal Michael J. Crescenz VAMC , Philadelphia, Pennsylvania, USA
                [5 ] departmentRheumatology Department , Dubai Hospital , Dubai, United Arab Emirates
                [6 ] departmentResearch and Development, MedImmune , LLC , Gaithersburg, Maryland, USA
                [7 ] departmentBiometrics & Information Sciences , AstraZeneca , Gaithersburg, Maryland, USA
                [8 ] departmentClinical Development , MedImmune, LLC , Gaithersburg, Maryland, USA
                [9 ] departmentInflammation, Autoimmunity & Neuroscience, Global Medicines Development , AstraZeneca , Gaithersburg, Maryland, USA
                Author notes
                [Correspondence to ] Professor Joan T Merrill; Joan-Merrill@ 123456omrf.org
                Article
                lupus-2018-000284
                10.1136/lupus-2018-000284
                6280909
                30588322
                324ec96f-15d8-4286-832f-bd290ea1d5b5
                © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                : 18 June 2018
                : 13 September 2018
                : 02 October 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004628, MedImmune;
                Categories
                Clinical Trials and Drug Discovery
                1506
                2250
                Custom metadata
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                arthritis,interferon,treatment
                arthritis, interferon, treatment

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