Abstracts of scientific contributions to GCOM 2019

Abstract

s of scientific contributions to GCOM 2019 Berlin, Germany. 27 30 March 2019 Published: 19 August 2019 I1 Selected highlights from the 3rd Global Conference of Myositis, Berlin Hector Chinoy, James B. Lilleker National Institute for Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, The University of Manchester (Manchester, UK); Department of Rheumatology, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre (Salford, UK); Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, The University of Manchester (Manchester, UK); Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust (Salford, UK) Correspondence: Hector Chinoy ([email protected]) BMC Rheumatology 2019, 3(Suppl 1):I1 March 2019 saw the 3rd Global Conference of Myositis at the historical European School of Management and Technology, Berlin, Germany, organized by Professors Werner Stenzel, Olivier Benveniste, Ichizo Nishino, and the Scientific and Organising Committee. The conference was well attended by 375 delegates from 30 different countries, including 20 invited speakers, A opportunity arose to fund a series of fellowships to junior researchers, from funds left over from the previous GCOM meeting at Potomac. There was a series of wonderful and enlightening talks from all over the world and from neighbouring disciplines. The conference started off with interesting pathology workshop detailing difficult cases. There then followed an introductory lecture by Voit on recent developments in the therapeutic approaches to neuromuscular diseases, including antisense therapy. Regulators are increasingly willing to accept ‘contemporary controls’ selected according to the same entry criteria to strengthen small placebo controls groups and improve power to detect change where short-term effect sizes are small. Discussion was also made about using myostatin, an activin 2b receptor binder, as a disease progression biomarker. Decreased levels of myostatin and downregulation of the myostatinactivin pathway are seen in neuromuscular disease, potentially also explaining the paucity of therapeutic benefits seen to date from myostatin receptor blockade. Kjaer discussed how age impairs the performance of the skeletal muscle and cardiovascular system. Three to six months of training can result in a 10-15% increase in strength/function, akin to 3-5 years of rejuvenation. Ageing can affect the transcriptional regulation of human skeletal muscle disuse atrophy, with the result that older people require four times as much time to recover from periods of immobility (1). This is associated with reduced anabolic signaling, and a decrease in number and responsiveness of satellite cells. Inclusion body myositis (IBM) was the subject of a number of talks. Wiehl discussed pathogenic mechanisms connecting inherited and acquired IBM, including disruptions in protein homeostasis and autophagy which have recently been interrogated using a targetted proteomic approach. (2). Britson described a xenograft model of sporadic IBM which shows impaired regeneration and TDP43 mislocalization. Greenberg discussed a potential therapeutic strategy of © The Author(s). 2019 Open Access This artic International License (http://creativecommons reproduction in any medium, provided you g the Creative Commons license, and indicate if (http://creativecommons.org/publicdomain/ze targeting highly differentiated T cells, particularly effector memory KLRG1+ cytotoxic T cells in IBM. There appears to be overlapping features between IBM and T cell large granular lymphocytic leukaemia, a malignancy of highly differentiated CD8 cytotoxic T cells which also exhibit upregulation of KLRG1. (3) Immune checkpoint inhibitors are increasingly being used to activate the immune system against malignant cells, particularly melanoma, but they can have autoimmune adverse effects, including myositis. Moslehi discussed his report in the Lancet where they identified 101 cases of severe myocarditis following treatment with immune checkpoint inhibitors (4). Of relevance to myologists, a substantial increase in incidence over time was noted. Klareskog gave an eloquent overview of the role of environmental factors, focusing on the lungs as a trigger of autoimmunity. He cited the analogy of rheumatoid arthritis, where a combination of genetics, epidemiological risk factors (including smoking, hormones, stress and the HPA axis), systemic immune dysregulation and disruption of mucosal biology create an at-risk population for development of autoimmunity (5). Smoking may predispose to antigenic peptide fragments being presented on the cell surface by HLA class II molecules (forming part of the common ancestral haplotype), and interact with autoaggressive CD4+ cells, for the subsequent development of anti-aminoacyl tRNA synthetase antibodies (6). The association of cancer and dermatomyositis was also a theme. Dani described register data from 2002 to 2016 in Sweden. Cancer risk in IIM patients is increased before diagnosis, reaches a peak one year prediagnosis, and continues to be significant until 10 years post-diagnosis. Site-specific cancer risk is highest for respiratory before diagnosis and the buccal cavity after. Even patients with IIM diagnoses other than DM are at risk of developing cancer. Oldroyd also described a temporal relationship with cancer and DM (7). Specifically, anti-TIF1gammapositive-associated malignancy occurs exclusively within the three year period on either side of DM onset, the risk being highest in those 39 years or younger. Within the anti-TIF1gamma-positive cohort, breast cancer was the most common malignancy (33%), followed by ovarian cancer (19%) and lymphoma (14%). Ovarian cancer constituted a significantly higher proportion of cancers in the anti-TIF1gamma-positive vs. -negative cases. It appears that possession of a specific anti-TIF1gamma IgG subtype is necessary to incur risk of cancer. A poster from Aussy (8) examined 51 antiTIF1gamma -positive patients, where 40 (78%) had cancer. Detection of antiTIF1gamma IgG2 was significantly associated with mortality (p=0.0011) and occurrence of cancer during the follow-up period, with a 100% positive predictive value of cancer when then mean fluorescence intensity of antiTIF1gamma IgG2 was >385. Patients with anti-MDA5 antibody-associated disease represent a challenging group where disease is often resistant to treatment and mortality is high. Toquet described a cohort of 121 anti-MDA5 antibodyassociated DM, where three subgroups with different outcomes were identified. Overall mortality was 27%. Cluster one had less arthralgia/ arthritis, but all had interstitial lung disease and there was a high frequency of mechanics’ hands. Cluster two, the “athro-cutaneo”-form, tended to have more arthralgia/arthritis, were less likely to be male and had a better prognosis. Cluster three, the “vasculo-cutaneo-muscular”le is distributed under the terms of the Creative Commons Attribution 4.0 .org/licenses/by/4.0/), which permits unrestricted use, distribution, and ive appropriate credit to the original author(s) and the source, provide a link to changes were made. The Creative Commons Public Domain Dedication waiver ro/1.0/) applies to the data made available in this article, unless otherwise stated. BMC Rheumatology 2019, 3(Suppl 1):31 Page 2 of 56 form, were more likely to be male, have skin vasculopathy (Raynaud’s, skin ulcers, digital necrosis, calcinosis), myositis and had an intermediate prognosis. Gono discussed an intensive treatment combination used for anti-MDA5 antibody-associated interstitial lung disease (9). This included high dose prednisolone, cyclosporine and intravenous cyclophosphamide. Peng discussed neopterin as a marker of macrophage activation. Increased neopterin levels have been noted in DM and in patients with MDA5. There was a positive correlation of neopterin with ferritin and markers of disease severity, and negative correlation with pulmonary function. Paik presented results of an open label study of the JAK inhibitor, Tofacinitib, in refractory DM, testing the hypothesis that the drug would inhibit the production or secretion of key pro-inflammatory chemokines e.g. CXCL9/10 to induce clinical remission (10). All 10 patients enrolled met the IMACS definition of improvement. Five of seven anti-TIF1gamma positive patients were moderate responders, and three of five were able to come off steroids. Generous financial support by Myositis UK formed the basis for a novel “speed-funding” event, where 17 grant applications were initially considered. Six junior researchers were then put forward to present a 15 minute funding proposal to a set of judges and the audience. Amidst a high-pressure atmosphere, the following were successful in securing funding: Kyla Britson, USA: The pathogenesis and treatment of inclusion body myositis in a xenograft model; Saskia Lassche, Netherlands; Inclusion body myositis on a chip, Erin Wilfong, USA; CD27‐CXCR4hiCD21lo cells in Jo1 positive IIM. Other highlights included a workshop for young researchers, a patient-centred workshop and further discussion about the establishment of a World Myositis Society. We now look forward now to the 4th GCOM which will provisionally be held in Prague, Czech Republic, in 2021. Sources of Funding: HC is supported by a grant from the Medical Research Council (MR/ N003322/1) and the NIHR Biomedical Research Centre Funding Scheme. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.