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      Tocilizumab may slow radiographic progression in patients with systemic or polyarticular-course juvenile idiopathic arthritis: post hoc radiographic analysis from two randomized controlled trials

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          Abstract

          Background

          Few clinical trials have investigated the prevention of radiographic progression in children with juvenile idiopathic arthritis treated with antirheumatic drugs. This study aimed to investigate radiographic progression in patients with systemic juvenile idiopathic arthritis (sJIA) and patients with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with the anti–interleukin-6 receptor antibody tocilizumab for 2 years in the TENDER and CHERISH randomized controlled trials, respectively.

          Methods

          Standard radiographs of both wrists and both hands in the posteroanterior view were obtained within 4 weeks of baseline and were repeated at weeks 52 ± 4 and 104 ± 4 in both trials. All films were scored by two independent readers using the adapted Sharp–van der Heijde (aSH) and Poznanski scoring methods. Although the Poznanski score indicates bone growth limitation or cartilage growth decrease, which are not the same as joint space narrowing in rheumatoid arthritis, its change reflects damage to cartilage. Therefore, impairment in the Poznanski score as well as the aSH score was considered as a measure of structural joint damage. Radiographic progression was defined as worsening of radiographic scores beyond the smallest detectable difference.

          Results

          Poznanski and aSH scores were available at baseline and at one or more postbaseline time points for 33 and 47 of 112 sJIA patients and 61 and 87 of 188 pcJIA patients, respectively, providing a representative subset of the study populations. The inter-reader and intra-reader agreement intra-class correlation coefficient was > 0.8. Median baseline Poznanski and aSH scores, respectively, were − 2.4 and 24.6 for sJIA patients and − 1.5 and 8.0 for pcJIA patients. Compared with baseline, aSH scores remained stable for all sJIA patients at week 52, whereas 9.4% of sJIA patients had radiographic progression according to Poznanski scores at week 52; at 104 weeks, radiographic progression according to aSH and Poznanski scores was observed in 5.4% and 11.5%, respectively. In pcJIA patients, radiographic progression from baseline at 52 weeks and at 104 weeks was 12.5% and 2.9%, respectively, using aSH scoring and 6.5% and 4%, respectively, using Poznanski scoring.

          Conclusion

          Tocilizumab may delay radiographic progression in children with sJIA and children with pcJIA.

          Trial registration

          Trial registration numbers and dates: TENDER, NCT00642460 (March 19, 2008); CHERISH, NCT00988221 (October 1, 2009)

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          Most cited references28

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          Juvenile idiopathic arthritis.

          Juvenile idiopathic arthritis is a broad term that describes a clinically heterogeneous group of arthritides of unknown cause, which begin before 16 years of age. This term encompasses several disease categories, each of which has distinct methods of presentation, clinical signs, and symptoms, and, in some cases, genetic background. The cause of disease is still poorly understood but seems to be related to both genetic and environmental factors, which result in the heterogeneity of the illness. Although none of the available drugs has a curative potential, prognosis has greatly improved as a result of substantial progresses in disease management. The most important new development has been the introduction of drugs such as anticytokine agents, which constitute a valuable treatment option for patients who are resistant to conventional antirheumatic agents. Further insights into the disease pathogenesis and treatment will be provided by the continuous advances in understanding of the mechanisms connected to the immune response and inflammatory process, and by the development of new drugs that are able to inhibit selectively single molecules or pathways.
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            Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab.

            To evaluate the ability of tocilizumab (a humanised anti-IL-6 receptor antibody) monotherapy to inhibit progression of structural joint damage in patients with RA. In a multi-centre, x ray reader-blinded, randomised, controlled trial, 306 patients with active RA of <5 years' duration were allocated to receive either tocilizumab monotherapy at 8 mg/kg intravenously every 4 weeks or conventional disease-modifying antirheumatic drugs (DMARDs) for 52 weeks. Radiographs of hands and forefeet were scored by the van der Heijde modified Sharp method. Patients had a mean disease duration of 2.3 years and a disease activity score in 28 joints of 6.5 at baseline. Mean total modified Sharp score (TSS) was 29.4, which was very high despite the relatively short disease duration. At week 52, the tocilizumab group showed statistically significantly less radiographic change in TSS (mean 2.3; 95% CI 1.5 to 3.2) than the DMARD group (mean 6.1; 95% CI 4.2 to 8.0; p<0.01). Tocilizumab monotherapy also improved signs and symptoms. The overall incidences of AEs were 89% and 82% (serious AEs: 18% and 13%; serious infections: 7.6% and 4.1%) in the tocilizumab and DMARD groups, respectively. Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA.
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              Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year.

              To assess the efficacy and safety of tocilizumab plus methotrexate (MTX) versus MTX alone in preventing structural joint damage and improving physical function and disease activity in patients with moderate-to-severe rheumatoid arthritis and inadequate responses to MTX. A total of 1,196 patients were enrolled in a 2-year, randomized, double-blind, placebo-controlled trial. Patients received tocilizumab (8 mg/kg or 4 mg/kg) or placebo every 4 weeks plus MTX. Rescue treatment was available from week 16. Results from year 1 are presented. Mean change in the total Genant-modified Sharp score was 0.29 and 0.34 with tocilizumab 8 mg/kg plus MTX and 4 mg/kg plus MTX, respectively, versus 1.13 with placebo plus MTX (P < 0.0001 for both comparisons). Analysis of variance of the area under the curve for change from baseline in the disability index of the Health Assessment Questionnaire showed greater decreases with tocilizumab 8 mg/kg and 4 mg/kg (-144.1 and -128.4 units, respectively) than with placebo (-58.1 units; P < 0.0001 for both comparisons). Proportions of patients with American College of Rheumatology 20%, 50%, and 70% improvement and with Disease Activity Score in 28 joints remission were higher in those receiving 8 mg/kg tocilizumab than in those receiving placebo (P < 0.0001 for all comparisons). The safety profile of tocilizumab was consistent with the profiles in previous studies. Infections were the most common adverse and serious adverse events. The findings of this study show that tocilizumab plus MTX results in greater inhibition of joint damage and improvement in physical function than does MTX alone. Tocilizumab has a well-characterized safety profile. Copyright © 2011 by the American College of Rheumatology.
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                Author and article information

                Contributors
                claramalattia@gaslini.org
                nicolaruperto@gaslini.org
                silvia.peder@inwind.it
                cioci@iol.it
                angelapistorio@gaslini.org
                carine.wouters@uzleuven.be
                Pavla.Dolezalova@vfn.cz
                berit.flato@medisin.uio.no
                stellag526@yahoo.com.ar
                gabriella.giancane@gmail.com
                chris.wells.cw1@roche.com
                wendy.douglass@roche.com
                Hermine.Brunner@cchmc.org
                fabrizio.debenedetti@opbg.net
                angeloravelli@gaslini.org
                Journal
                Arthritis Res Ther
                Arthritis Res. Ther
                Arthritis Research & Therapy
                BioMed Central (London )
                1478-6354
                1478-6362
                10 September 2020
                10 September 2020
                2020
                : 22
                : 211
                Affiliations
                [1 ]GRID grid.5606.5, ISNI 0000 0001 2151 3065, Università degli Studi di Genova, ; Genoa, Italy
                [2 ]IRCCS Istituto Giannina Gaslini, Clinica Pediatrica e Reumatologia, PRINTO, Via G. Gaslini 5, 16147 Genoa, Italy
                [3 ]IRCCS Istituto Giannina Gaslini, Servizio di Epidemiologia e Biostatistica, Genoa, Italy
                [4 ]GRID grid.410569.f, ISNI 0000 0004 0626 3338, University Hospital Gasthuisberg, ; Leuven, Belgium
                [5 ]GRID grid.4491.8, ISNI 0000 0004 1937 116X, General University Hospital and First Faculty of Medicine, , Charles University, ; Prague, Czech Republic
                [6 ]GRID grid.55325.34, ISNI 0000 0004 0389 8485, Oslo University Hospital and University of Oslo, ; Oslo, Norway
                [7 ]Hospital Sor Maria Ludovica, La Plata, Argentina
                [8 ]GRID grid.419227.b, Roche Products Ltd., ; Welwyn Garden City, UK
                [9 ]GRID grid.239573.9, ISNI 0000 0000 9025 8099, Cincinnati Children’s Hospital Medical Center, ; Cincinnati, OH USA
                [10 ]GRID grid.414125.7, ISNI 0000 0001 0727 6809, IRCCS Ospedale Pediatrico Bambino Gesú, ; Rome, Italy
                [11 ]GRID grid.448878.f, ISNI 0000 0001 2288 8774, Sechenov First Moscow State Medical University, ; Moscow, Russian Federation
                Author information
                http://orcid.org/0000-0001-9658-0385
                Article
                2303
                10.1186/s13075-020-02303-y
                7488325
                32912276
                c0c8b9e4-d994-4dd3-bef3-233acda31556
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 18 October 2019
                : 24 August 2020
                Funding
                Funded by: F. Hoffmann-La Roche Ltd.
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2020

                Orthopedics
                biologicals,disease-modifying antirheumatic drugs (dmards),tocilizumab,systemic juvenile idiopathic arthritis,polyarticular-course juvenile idiopathic arthritis

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