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      Sifalimumab, a Human Anti–Interferon-α Monoclonal Antibody, in Systemic Lupus Erythematosus: A Phase I Randomized, Controlled, Dose-Escalation Study : A Phase I Randomized, Controlled, Dose-Escalation Study

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          Abstract

          Objective

          To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE).

          Methods

          In this multicenter, double-blind, placebo-controlled, sequential dose-escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment-emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed.

          Results

          Of 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate-to-severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment-emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n = 4) versus 2.5% (n = 1). Serum sifalimumab concentrations increased in a linear and dose-proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline.

          Conclusion

          The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.

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          Most cited references28

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          Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.

          M Hochberg (1997)
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            Combined oral contraceptives in women with systemic lupus erythematosus.

            Oral contraceptives are rarely prescribed for women with systemic lupus erythematosus, because of concern about potential negative side effects. In this double-blind, randomized, noninferiority trial, we prospectively evaluated the effect of oral contraceptives on lupus activity in premenopausal women with systemic lupus erythematosus. A total of 183 women with inactive (76 percent) or stable active (24 percent) systemic lupus erythematosus at 15 U.S. sites were randomly assigned to receive either oral contraceptives (triphasic ethinyl estradiol at a dose of 35 microg plus norethindrone at a dose of 0.5 to 1 mg for 12 cycles of 28 days each; 91 women) or placebo (92 women) and were evaluated at months 1, 2, 3, 6, 9, and 12. Subjects were excluded if they had moderate or high levels of anticardiolipin antibodies, lupus anticoagulant, or a history of thrombosis. The primary end point, a severe lupus flare, occurred in 7 of 91 subjects receiving oral contraceptives (7.7 percent) as compared with 7 of 92 subjects receiving placebo (7.6 percent). The 12-month rates of severe flare were similar: 0.084 for the group receiving oral contraceptives and 0.087 for the placebo group (P=0.95; upper limit of the one-sided 95 percent confidence interval for this difference, 0.069, which is within the prespecified 9 percent margin for noninferiority). Rates of mild or moderate flares were 1.40 flares per person-year for subjects receiving oral contraceptives and 1.44 flares per person-year for subjects receiving placebo (relative risk, 0.98; P=0.86). In the group that was randomized to receive oral contraceptives, there was one deep venous thrombosis and one clotted graft; in the placebo group, there was one deep venous thrombosis, one ocular thrombosis, one superficial thrombophlebitis, and one death (after cessation of the trial). Our study indicates that oral contraceptives do not increase the risk of flare among women with systemic lupus erythematosus whose disease is stable. Copyright 2005 Massachusetts Medical Society.
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              The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus.

              To develop and perform an initial validation of a damage index for systemic lupus erythematosus (SLE). A list of items considered to reflect damage in SLE was generated through a nominal group process. A consensus as to which items to be included in an index was reached, together with rules for ascertainment. Each center submitted 2 assessments, 5 years apart, on 2 patients with active and 2 with inactive disease, of whom 1 had increased damage and the other had stable disease. Analysis of variance was used to test the factors physician, time, amount of damage, and activity status. Nineteen physicians completed the damage index on 42 case scenarios. The analysis revealed that the damage index could identify changes in damage seen in patients with both active and inactive disease. Patients who had active disease at both time points had a higher increase in damage. There was good agreement among the physicians on the assessment of damage in these patients. This damage index for SLE records damage occurring in patients with SLE regardless of its cause. The index was demonstrated to have content, face, criterion, and discriminant validity.
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                Author and article information

                Journal
                Arthritis Rheum
                Arthritis Rheum
                art
                Arthritis and Rheumatism
                Wiley Subscription Services, Inc., A Wiley Company (Hoboken )
                0004-3591
                1529-0131
                April 2013
                28 March 2013
                : 65
                : 4
                : 1011-1021
                Affiliations
                [1 ]Johns Hopkins University School of Medicine Baltimore, Maryland
                [2 ]Cedars-Sinai Medical Center and David Geffen School of Medicine, University of California Los Angeles
                [3 ]Centro Medico Privado de Reumatologia Tucumán, Argentina
                [4 ]Pinnacle Research Group Anniston, Alabama
                [5 ]University of California at San Diego La Jolla
                [6 ]Organización Médica de Investigación Buenos Aires, Argentina
                [7 ]East Bay Rheumatology Research Institute San Leandro, California
                [8 ]MedImmune, LLC Gaithersburg, Maryland
                Author notes

                ClinicalTrials.gov identifier: NCT00482989.

                Supported by MedImmune, LLC.

                Dr. Petri has received consulting fees from GlaxoSmithKline and Human Genome Sciences (less than $10,000 each). Dr. Chindalore has received speaking fees from Pfizer, Roche, and Eli Lilly (more than $10,000 each). Dr. Kalunian has received consulting fees from Genentech, Merck Serono, Anthera, Questcor, Ambit, and Novo Nordisk (less than $10,000 each). Drs. Robbie, White, Higgs, Yao, Wang, and Greth are employees of MedImmune, LLC and own stock or stock options in AstraZeneca. Dr. Yao is a coinventor on a diagnostic patent for sifalimumab in systemic lupus erythematosus filed by MedImmune, LLC.

                [†]

                Dr. Ethgen is deceased.

                Address correspondence to Michelle Petri, MD, MPH, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 7500, Baltimore, MD 21205. E-mail: mpetri@ 123456jhmi.edu .
                Article
                10.1002/art.37824
                3654174
                23400715
                0d126a6b-74a7-4f59-ac5a-82324536f0bf
                Copyright © 2013 by the American College of Rheumatology

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                History
                : 09 March 2012
                : 04 December 2012
                Categories
                Systemic Lupus Erythematosus

                Rheumatology
                Rheumatology

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