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      Brief Report: A Randomized, Double‐Blind, Parallel‐Group, Placebo‐Controlled, Multiple‐Dose Study to Evaluate AMG 557 in Patients With Systemic Lupus Erythematosus and Active Lupus Arthritis

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          Abstract

          Objective

          To evaluate the safety and potential efficacy of AMG 557, a fully human antibody directed against the inducible T cell costimulator ligand (ICOSL) in patients with systemic lupus erythematosus ( SLE) with arthritis.

          Methods

          In this phase Ib, randomized, double‐blind, placebo‐controlled study, patients received AMG 557 210 mg (n = 10) or placebo (n = 10) weekly for 3 weeks, then every other week for 10 additional doses. The corticosteroid dosage was tapered to ≤7.5 mg/day by day 85, and immunosuppressants were discontinued by day 29. Primary end points on day 169 were safety, immunogenicity, the Lupus Arthritis Response Index ( LARI; defined by a reduction in the tender and swollen joint counts), ≥1‐letter improvement in the musculoskeletal domain of the British Isles Lupus Assessment Group ( BILAG) index, and medication discontinuation. The secondary/exploratory end points were changes in the tender and swollen joint counts, BILAG index scores (musculoskeletal, global), and the Systemic Lupus Erythematosus Disease Activity Index ( SLEDAI).

          Results

          The incidence of adverse events, most of which were mild, was similar between groups. LARI responses occurred in 3 of 10 patients receiving AMG 557 and 1 of 10 patients receiving placebo ( P = 0.58). More patients in the AMG 557 group achieved a ≥4‐point improvement in the SLEDAI score on day 169 (7 of 10 patients) compared with the placebo group (2 of 10 patients) ( P = 0.07). Patients treated with AMG 557 (versus placebo) had greater improvements from baseline in the global BILAG index scores (–36.3% versus –24.7%) and the SLEDAI score (–47.8% versus –10.7%) and in tender (–22.8% versus –13.5%) and swollen (–62.1% versus –7.8%) joint counts on day 169.

          Conclusion

          AMG 557 showed safety and potential efficacy, supporting further evaluation of the clinical efficacy of ICOSL blockade in patients with SLE.

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          Most cited references8

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          Follicular helper T cells in immunity and systemic autoimmunity.

          Meggan Craft (2012)
          Follicular helper T (T(FH)) cells are essential for B-cell maturation and immunoglobulin production after immunization with thymus-dependent antigens. Nevertheless, the development and function of T(FH) cells have been less clearly defined than classic CD4(+) effector T-cell subsets, including T-helper-1 (T(H)1), T(H)2 and T(H)17 cells. As such, our understanding of the genesis of T(FH) cells in humans and their role in the development of autoimmunity remains incomplete. However, evidence from animal models of systemic lupus erythematosus (SLE) and patients with systemic autoimmune diseases suggests that these cells are necessary for pathogenic autoantibody production, in a manner analogous to their role in promotion of B-cell maturation during normal immune responses. In this Review, I discuss the findings that have increased our knowledge of T(FH)-cell development and function in normal and aberrant immune responses. Such information might improve our understanding of autoimmune diseases, such as SLE, and highlights the potential of T(FH) cells as therapeutic targets in these diseases.
          Article 0 comments Cited 130 times – based on 0 reviews     Review now
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            Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study.

            C Yarboro, Yuko Shirota, G Illei … (2010)
            To assess the safety of interleukin-6 receptor inhibition and to collect preliminary data on the clinical and immunologic efficacy of tocilizumab in patients with systemic lupus erythematosus (SLE). In an open-label phase I dosage-escalation study, 16 patients with mild-to-moderate disease activity were assigned to receive 1 of 3 doses of tocilizumab given intravenously every other week for 12 weeks (total of 7 infusions): 2 mg/kg in 4 patients, 4 mg/kg in 6 patients, or 8 mg/kg in 6 patients. Patients were then monitored for an additional 8 weeks. The infusions were well tolerated. Tocilizumab treatment led to dosage-related decreases in the absolute neutrophil count, with a median decrease of 38% in the 4 mg/kg dosage group and 56% in the 8 mg/kg dosage group. Neutrophil counts returned to normal after cessation of treatment. One patient was withdrawn from the study because of neutropenia. Infections occurred in 11 patients; none was associated with neutropenia. Disease activity showed significant improvement, with a decrease of > or =4 points in the modified Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index score in 8 of the 15 evaluable patients. Arthritis improved in all 7 patients who had arthritis at baseline and resolved in 4 of them. Levels of anti-double-stranded DNA antibodies decreased by a median of 47% in patients in the 4 mg/kg and 8 mg/kg dosage groups, with a 7.8% decrease in their IgG levels. These changes, together with a significant decrease in the frequency of circulating plasma cells, suggest a specific effect of tocilizumab on autoantibody-producing cells. Although neutropenia may limit the maximum dosage of tocilizumab in patients with SLE, the observed clinical and serologic responses are promising and warrant further studies to establish the optimal dosing regimen and efficacy.
            Article 0 comments Cited 123 times – based on 0 reviews     Review now
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              Revised British Isles Lupus Assessment Group 2004 index: a reliable tool for assessment of systemic lupus erythematosus activity.

              Chee-Seng Yee, Vernon Farewell, David A Isenberg … (2006)
              To test the interrater reliability of the revised British Isles Lupus Assessment Group 2004 (BILAG-2004) index for the assessment of systemic lupus erythematosus (SLE) activity. Patients with SLE were recruited from 11 centers. Two physician raters separately assessed the patients' disease activity using the BILAG-2004 index in routine clinical practice. Scores ranged from A (for very active disease) to E (for inactivity). Two reliability exercises were performed. Changes were made to the index after the first exercise (E1), and additional training was provided to the raters before the second exercise (E2). E1 and E2 involved 12 and 14 raters, respectively. Interrater reliability was assessed using kappa statistics and intraclass correlation coefficients. Levels of agreement and the extent of major disagreement were also examined. Major disagreement was defined as a score difference between raters of A versus C, D, or E or B versus D or E. For each exercise, 97 patients were recruited. In E1, the mean age of the patients was 42.3 years (range 18.5-82.2 years), 89.7% were women, and 74.2% were white, 8.2% were Afro-Caribbean, and 13.4% were South Asian, and in E2, the mean age was 43.7 years (range 17.7-75 years), 90.7% were women, and 68% were white, 15.5% were Afro-Caribbean, and 11.3% were South Asian. The mean disease duration was 9.4 years (range 0-32.1 years) for patients in E1 and 10 years (range 0-34.8 years) in E2. There was improvement in the interrater reliability and the level of agreement from E1 to E2. Further improvement was achieved after removal of poorly performing items. The BILAG-2004 index is a reliable tool to assess SLE activity. The use of a well-defined glossary and training of raters are essential to ensure the optimal performance of the index.
              Article 0 comments Cited 38 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                James B. Chung: chung@amgen.com
                Journal
                Journal ID (nlm-ta): Arthritis Rheumatol
                Journal ID (doi): 10.1002/(ISSN)2326-5205
                Journal ID (publisher-id): ART
                Title: Arthritis & Rheumatology (Hoboken, N.j.)
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 2326-5191
                ISSN (Electronic): 2326-5205
                Publication date (Electronic): 25 May 2018
                Publication date (Print): July 2018
                Volume: 70
                Issue: 7 ( doiID: 10.1002/art.v70.7 )
                Pages: 1071-1076
                Affiliations
                [ 1 ] Amgen Thousand Oaks California
                [ 2 ] Hôpital Pitié‐Salpêtrière Paris France
                [ 3 ] International Medical University Kuala Lumpur Malaysia
                [ 4 ] Charité Universitätsmedizin Berlin Berlin Germany
                [ 5 ] Oklahoma Medical Research Foundation Oklahoma City
                Author notes
                [*] [* ]Address correspondence to James B. Chung, MD, PhD, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320. E‐mail: chung@ 123456amgen.com .
                Article
                Publisher ID: ART40479
                DOI: 10.1002/art.40479
                PMC ID: 6032945
                PubMed ID: 29513931
                SO-VID: 0ba4f8d4-2bdc-405e-8281-ff56159c03e2
                Copyright © © 2018 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Date received : 19 October 2017
                Date accepted : 27 February 2018
                Page count
                Figures: 1, Tables: 2, Pages: 6, Words: 4627
                Funding
                Funded by: Amgen
                Funded by: AstraZeneca
                Funded by: MedImmune
                Categories
                Subject: Brief Report
                Subject: Systemic Lupus Erythematosus
                Custom metadata
                source-schema-version-number 2.0
                component-id art40479
                cover-date July 2018
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.3 mode:remove_FC converted:05.07.2018

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