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

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          Abstract

          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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          Most cited references15

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          The CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index): an outcome instrument for cutaneous lupus erythematosus.

          We developed and validated a measurement instrument (CLASI-Cutaneous Lupus Erythematosus Disease Area and Severity Index) for lupus erythematosus that could be used in clinical trials. The instrument has separate scores for damage and activity. A group of seven American Dermato-Rheumatologists and the "American College of Rheumatology Response Criteria Committee on SLE (systemic lupus erythematosus)" assessed content validity. After a preliminary session, we conducted standardized interviews with the raters and made slight changes to the instrument. The final instrument was evaluated by five dermatologists and six residents who scored nine patients to estimate inter- and intra-rater reliability in two sessions. Consultation with experts has established content validity of the instrument. Reliability studies demonstrated an intra-class correlation coefficient (ICC) for inter-rater reliability of 0.86 for the activity score (95% confidence interval (CI) = 0.73-0.99) and of 0.92 for the damage score (95% CI = 0.85-1.00). The Spearman's rho (Sp) for intra-rater reliability for the activity score was 0.96 (95% CI = 0.89 to 1.00) and for the damage score Sp was 0.99 (95% CI = 0.97-1.00). Clinical responsiveness needs to be evaluated in a prospective clinical trial, which is ongoing.
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            Glucocorticoid use and abuse in SLE

            Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressive agents. They act by two different mechanisms: the genomic and the non-genomic pathways. The genomic pathway is considered responsible for many adverse effects of GCs, most of them are time and dose dependent. Observational studies support a relationship between GCs and damage in SLE. GCs have been associated with the development of osteoporosis, osteonecrosis, cataracts, hyperglycaemia, coronary heart disease and cognitive impairment, among others. Although no clinical trial has compared high vs low doses of GCs, some studies have shown the efficacy of medium doses in severe forms of SLE. The dose below which treatment can be considered safe has not been defined, but daily doses <7.5 mg of prednisone seem to minimize adverse effects. Combination therapy with HCQ and the judicious use of immunosuppressive drugs help to keep prednisone therapy within those limits.
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              The type I interferon system in the development of lupus.

              The type I interferon (IFN) system induces inhibition of viral replication, but can also activate the innate and adaptive immune system. An important role of the type I IFN system in autoimmune diseases, including lupus, is suggested by the observation that these disorders display a prominent over-expression of type I IFN regulated genes. The development of autoimmune diseases in some individuals treated with IFN-α directly supports a pivotal role for this cytokine in breaking tolerance and inducing autoimmune reactions. A genetic setup that promotes type I IFN production and/or response and the presence of endogenous inducers of IFN-α production have been described in patients with lupus. Several known environmental risk factors for development of lupus or disease flares may contribute to the ongoing type I IFN production. In the present review we will describe the possible role of the type I IFN system in the lupus disease process. The possible connection between the type I IFN system and some environmental and genetic risk factors for lupus is also discussed. Copyright © 2011 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                RFurie@northwell.edu
                Journal
                Arthritis Rheumatol
                10.1002/(ISSN)2326-5205
                ART
                Arthritis & Rheumatology (Hoboken, N.j.)
                John Wiley and Sons Inc. (Hoboken )
                2326-5191
                2326-5205
                28 January 2017
                February 2017
                : 69
                : 2 ( doiID: 10.1002/art.v69.2 )
                : 376-386
                Affiliations
                [ 1 ]Hofstra Northwell School of Medicine, Northwell Health New York New York
                [ 2 ]King's College London and St. Thomas’ Hospital LondonUK
                [ 3 ]Oklahoma Medical Research Foundation Oklahoma City
                [ 4 ]Philadelphia VA Medical Center and University of Pennsylvania Philadelphia
                [ 5 ]University of California at San Diego School of Medicine La Jolla California
                [ 6 ]MedImmune Gaithersburg Maryland
                [ 7 ]Regenxbio Rockville Maryland
                Author notes
                [*] [* ]Address correspondence to Richard Furie, MD, Division of Rheumatology, Northwell Health, 865 Northern Boulevard, Great Neck, NY 11021. E‐mail: RFurie@ 123456northwell.edu .
                Article
                ART39962
                10.1002/art.39962
                5299497
                28130918
                3b844a61-1b32-48f3-a260-5694b75c70e9
                © 2016 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 29 April 2016
                : 13 October 2016
                Page count
                Figures: 3, Tables: 3, Pages: 11, Words: 6582
                Funding
                Funded by: MedImmune
                Categories
                Systemic Lupus Erythematosus
                Systemic Lupus Erythematosus
                Custom metadata
                2.0
                art39962
                February 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.5 mode:remove_FC converted:09.02.2017

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