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To identify clinical factors associated with cancer risk in the idiopathic inflammatory myopathies (IIMs) and to systematically review the existing evidence related to cancer screening. A systematic literature search was carried out on Medline, Embase and Scopus. Cancer risk within the IIM population (i.e. not compared with the general population) was expressed as risk ratios (RR) for binary variables and weighted mean differences (WMD) for continuous variables. Evidence relating to cancer screening practices in the IIMs were synthesized via narrative review. Sixty-nine studies were included in the meta-analysis. DM subtype (RR 2.21), older age (WMD 11.19), male sex (RR 1.53), dysphagia (RR 2.09), cutaneous ulceration (RR 2.73) and anti-transcriptional intermediary factor-1 gamma positivity (RR 4.66) were identified as being associated with significantly increased risk of cancer. PM (RR 0.49) and clinically amyopathic DM (RR 0.44) subtypes, Raynaud's phenomenon (RR 0.61), interstitial lung disease (RR 0.49), very high serum creatine kinase (WMD −1189.96) or lactate dehydrogenase (WMD −336.52) levels, and anti-Jo1 (RR 0.45) or anti-EJ (RR 0.17) positivity were identified as being associated with significantly reduced risk of cancer. Nine studies relating to IIM-specific cancer screening were included. CT scanning of the thorax, abdomen and pelvis appeared to be effective in identifying underlying asymptomatic cancers. Cancer risk factors should be evaluated in patients with IIM for risk stratification. Screening evidence is limited but CT scanning could be useful. Prospective studies and consensus guidelines are needed to establish cancer screening strategies in IIM patients

Objective To investigate the human leukocyte antigen (HLA) association with anti-synthetase syndrome (ASSD). Methods We conducted the largest immunogenetic HLA-DRB1 and HLA-B study to date in a homogeneous cohort of 168 Caucasian patients with ASSD and 486 ethnically matched healthy controls by sequencing-based-typing. Results A statistically significant increase of HLA-DRB1*03:01 and HLA-B*08:01 alleles in patients with ASSD compared to healthy controls was disclosed (26.2% versus 12.2%, P = 1.56E–09, odds ratio–OR [95% confidence interval–CI] = 2.54 [1.84–3.50] and 21.4% versus 5.5%, P = 18.95E–18, OR [95% CI] = 4.73 [3.18–7.05]; respectively). Additionally, HLA-DRB1*07:01 allele was significantly decreased in patients with ASSD compared to controls (9.2% versus 17.5%, P = 0.0003, OR [95% CI] = 0.48 [0.31–0.72]). Moreover, a statistically significant increase of HLA-DRB1*03:01 allele in anti-Jo-1 positive compared to anti-Jo-1 negative patients with ASSD was observed (31.8% versus 15.5%, P = 0.001, OR [95% CI] = 2.54 [1.39–4.81]). Similar findings were observed when HLA carrier frequencies were assessed. The HLA-DRB1*03:01 association with anti-Jo-1 was unrelated to smoking history. No HLA differences in patients with ASSD stratified according to the presence/absence of the most representative non-anti-Jo-1 anti-synthetase autoantibodies (anti-PL-12 and anti-PL-7), arthritis, myositis or interstitial lung disease were observed. Conclusions Our results support the association of the HLA complex with the susceptibility to ASSD.

OBJECTIVES: Although classification systems and scores for capillaroscopy interpretation have been published, there is a lack of homogenization for the procedure, especially in the way and place the images are taken, the counting of the capillaries and the measuring of their size. Our objective is to provide a deep learning-based software to obtain objective and exhaustive data for the whole nailfold without increasing the time or effort needed to do the examination, or requiring expensive equipment. METHODS: An automated software to count nailfold capillaries has been designed, through an exploratory image dataset of 2,713 images with 18,000 measurements of 3 different types. Subsequently, application rules have been created to detect the morphology of nailfold videocapillaroscopy images, through a training set of images. The software reliability has been evaluated with standard metrics used in the machine learning field for object detection tasks, comparing automatic and manual counting on the same NVC images. RESULTS: A mean average precision (mAP) of 0.473 is achieved for detecting and classifying capillaries and haemorrhages by their shape, and a mAP of 0.515 is achieved for detecting and classifying capillaries by their size. A precision of 83.84% and a recall of 92.44% in the identification of capillaries was estimated. CONCLUSIONS: Deep learning is a useful tool in nailfold videocapillaroscopy that allows to analyse objectively and homogeneously images taken with multiple devices. It should make the assessment of the capillary morphology in nailfold video capillaroscopy easier, quicker, more complete and accessible to everyone.

Objectives To identify clinical factors associated with cancer risk in the idiopathic inflammatory myopathies (IIMs) and to systematically review the existing evidence related to cancer screening. Methods A systematic literature search was carried out on Medline, Embase and Scopus. Cancer risk within the IIM population (i.e. not compared with the general population) was expressed as risk ratios (RR) for binary variables and weighted mean differences (WMD) for continuous variables. Evidence relating to cancer screening practices in the IIMs were synthesized via narrative review. Results Sixty-nine studies were included in the meta-analysis. DM subtype (RR 2.21), older age (WMD 11.19), male sex (RR 1.53), dysphagia (RR 2.09), cutaneous ulceration (RR 2.73) and anti-transcriptional intermediary factor-1 gamma positivity (RR 4.66) were identified as being associated with significantly increased risk of cancer. PM (RR 0.49) and clinically amyopathic DM (RR 0.44) subtypes, Raynaud’s phenomenon (RR 0.61), interstitial lung disease (RR 0.49), very high serum creatine kinase (WMD −1189.96) or lactate dehydrogenase (WMD −336.52) levels, and anti-Jo1 (RR 0.45) or anti-EJ (RR 0.17) positivity were identified as being associated with significantly reduced risk of cancer. Nine studies relating to IIM-specific cancer screening were included. CT scanning of the thorax, abdomen and pelvis appeared to be effective in identifying underlying asymptomatic cancers. Conclusion Cancer risk factors should be evaluated in patients with IIM for risk stratification. Screening evidence is limited but CT scanning could be useful. Prospective studies and consensus guidelines are needed to establish cancer screening strategies in IIM patients.

Background: From 2005 to 2010, we conducted 2 randomized studies on a journal (Medicina Clínica), where we took manuscripts received for publication and randomly assigned them to either the standard editorial process or to additional processes. Both studies were based on the use of methodological reviewers and reporting guidelines (RG). Those interventions slightly improved the items reported on the Manuscript Quality Assessment Instrument (MQAI), which assesses the quality of the research report. However, masked evaluators were able to guess the allocated group in 62% (56/90) of the papers, thus presenting a risk of detection bias. In this post-hoc study, we analyse whether those interventions that were originally designed for improving the completeness of manuscript reporting may have had an effect on the number of citations, which is the measured outcome that we used. Methods: Masked to the intervention group, one of us used the Web of Science (WoS) to quantify the number of citations that the participating manuscripts received up December 2016. We calculated the mean citation ratio between intervention arms and then quantified the uncertainty of it by means of the Jackknife method, which avoids assumptions about the distribution shape. Results: Our study included 191 articles (99 and 92, respectively) from the two previous studies, which all together received 1336 citations. In both studies, the groups subjected to additional processes showed higher averages, standard deviations and annual rates. The intervention effect was similar in both studies, with a combined estimate of a 43% (95% CI: 3 to 98%) increase in the number of citations. Conclusions: We interpret that those effects are driven mainly by introducing into the editorial process a senior methodologist to find missing RG items. Those results are promising, but not definitive due to the exploratory nature of the study and some important caveats such as: the limitations of using the number of citations as a measure of scientific impact; and the fact that our study is based on a single journal. We invite journals to perform their own studies to ascertain whether or not scientific repercussion is increased by adhering to reporting guidelines and further involving statisticians in the editorial process. DGA, JAG and EC belong to MiRoR (Methods in Research on Research), which has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 676207. EC and JC are partially supported by the grants MTM2015–64465-C2–1-R (MINECO/FEDER, UE) from the Secretaría de Estado de Investigación, Desarrollo e Innovación del Ministerio de Economía y Competitividad (Spain) and through grant 2017 SGR 622 from the Departament d’Economia i Coneixement de la Generalitat de Catalunya (Spain). The funding bodies had no role in the study design, data collection and analysis, results interpretation, or in writing the manuscript.

Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of onset, characteristics, clustering of triad findings, and survival of 828 ASSD patients (593 anti-Jo1, 95 anti-PL7, 84 anti-PL12, 38 anti-EJ, and 18 anti-OJ), referring to AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group's cohort. Comparisons were performed first between all ARS cases and then, in the case of significance, while using anti-Jo1 positive patients as the reference group. The characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The "ex-novo" occurrence of triad findings was only reduced in the anti-PL12-positive cohort, however, it occurred in a clinically relevant percentage of patients (30%). Moreover, survival was not influenced by the underlying anti-aminoacyl tRNA synthetase antibodies' positivity, which confirmed that antisynthetase syndrome is a heterogeneous condition and that antibody specificity only partially influences the clinical presentation and evolution of this condition. ispartof: JOURNAL OF CLINICAL MEDICINE vol:8 issue:11 ispartof: location:Switzerland status: published

OBJECTIVE: The subsarcolemmal accumulation of p62 aggregates in myofibres has been proposed to be characteristic of s poradic inclusion body myositis (sIBM). The objective of this study was to analyse the patterns and prevalence of p62 immunostaining and to quantitate p62 gene expression in muscle biopsies from a large number of patients with different types of myopathic and neurogenic disorders. METHODS: For the p62 immunostaining analysis, all patients with a muscle biopsy immunostained for p62 at the Johns Hopkins Neuromuscular Pathology Laboratory from 2013 to 2017 were included (n=303). The prevalence and pattern of p62 immunostaining were compared between patients with histologically normal muscle (n=29), inflammatory myopathies (n=136), non-inflammatory myopathies (n=53), and neurogenic disorders (n=85). p62 expression levels were analysed using an existing RNAseq dataset including data from dermatomyositis (DM; n=39), immune-mediated necrotising myopathy (IMNM; n=49), antisynthetase syndrome (AS; n=18), and sIBM (n=23) patients as well as 20 histologically normal muscle biopsies. RESULTS: p62 staining was absent in normal biopsies, but present in biopsies from those with polymyositis (29%), non-inflammatory myopathies (all

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Objectives: The study aimed to develop evidence-based recommendations for the treatment of rapidly progressive interstitial lung disease (RPILD) associated with the anti-Melanoma Differentiation-Associated Gene 5-positive dermatomyositis (DM) syndrome. Methods: The task force comprised an expert panel of specialists in rheumatology, intensive care medicine, pulmonology, immunology, and internal medicine. The study was carried out in two phases: identifying key areas in the management of DM-RPILD syndrome and developing a set of recommendations based on a review of the available scientific evidence. Four specific questions focused on different treatment options were identified. Relevant publications in English, Spanish or French up to April 2018 were searched systematically for each topic using PubMed (MEDLINE), EMBASE, and Cochrane Library (Wiley Online). The experts used evidence obtained from these studies to develop recommendations. Results: A total of 134 studies met eligibility criteria and formed the evidentiary basis for the recommendations regarding immunosuppressive therapy and complementary treatments. Overall, there was general agreement on the initial use of combined immunosuppressive therapy. Combination of high-dose glucocorticoids and calcineurin antagonists with or without cyclophosphamide is the first choice. In the case of calcineurin antagonist contraindication or treatment failure, switching or adding other immunosuppressants may be individualized. Plasmapheresis, polymyxin B hemoperfusion and/or intravenous immunoglobulins may be used as rescue options. ECMO should be considered in life-threatening situations while waiting for a clinical response or as a bridge to lung transplant. Conclusions: Thirteen recommendations regarding the treatment of the anti-MDA5 positive DM-RPILD were developed using research-based evidence and expert opinion. This project was supported by Spanish Rheumatology Society and Spanish Society of Internal Medicine (GEAS, Study Group on Autoimmune Diseases).

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MUC5B rs35705950 (G/T) is strongly associated with idiopathic pulmonary fibrosis (IPF) and also contributes to the risk of interstitial lung disease (ILD) in rheumatoid arthritis (RA-ILD) and chronic hypersensitivity pneumonitis (CHP). Due to this, we evaluated the implication of MUC5B rs35705950 in antisynthetase syndrome (ASSD), a pathology characterised by a high ILD incidence. 160 patients with ASSD (142 with ILD associated with ASSD [ASSD-ILD+]), 232 with ILD unrelated to ASSD (comprising 161 IPF, 27 RA-ILD and 44 CHP) and 534 healthy controls were genotyped. MUC5B rs35705950 frequency did not significantly differ between ASSD-ILD+ patients and healthy controls nor when ASSD patients were stratified according to the presence/absence of anti Jo-1 antibodies or ILD. No significant differences in MUC5B rs35705950 were also observed in ASSD-ILD+ patients with a usual interstitial pneumonia (UIP) pattern when compared to those with a non-UIP pattern. However, a statistically significant decrease of MUC5B rs35705950 GT, TT and T frequencies in ASSD-ILD+ patients compared to patients with ILD unrelated to ASSD was observed. In summary, our study does not support a role of MUC5B rs35705950 in ASSD. It also indicates that there are genetic differences between ILD associated with and that unrelated to ASSD, This study was partially supported by grants from the Foundation for Research in Rheumatology (FOREUM). RL-M is a recipient of a Miguel Servet type I programme fellowship from the ‘Instituto de Salud Carlos III’ (ISCIII), cofunded by the European Social Fund (ESF, ‘Investing in your future’) (grant CP16/00033). SR-M is supported by funds of the RETICS Program (RD16/0012/0009), co-funded by the European Regional Development Fund (ERDF). VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). VM is supported by funds of a Miguel Servet type I programme (grant CP16/00033) (ISCIII, co-funded by ESF). LL-G is supported by funds of PI18/00042 (ISCIII, co-funded by ERDF). OG is Staff Personnel of Xunta de Galicia (Servizo Galego de Saude, SERGAS) through a research-staff stabilization contract (ISCIII/SERGAS). OG,is member of RETICS Programme, RD16/0012/0014 (RIER: Red de Investigación en Inflamación y Enfermedades Reumáticas) via Instituto de Salud Carlos III (ISCIII) and FEDER. The work of OG (PI17/00409), was funded by Instituto de Salud Carlos III and FEDER. OG is a beneficiary of a project funded by Research Executive Agency of the European Union in the framework of MSCA-RISE Action of the H2020 Programme (Project number 734899). OG is beneficiary of a grant funded by Xunta de Galicia, Consellería de Educación, Universidade e Formación Profesional and Consellería de Economía, Emprego e Industria (GAIN), GPC IN607B2019/10

It is well established that myositis is associated with cancer, although it took decades to consistently recognize this relationship because of the low incidence of inflammatory myopathies in the population. This association can be a challenge for clinicians who must decide when and how to implement screening for occult cancer in their myositis patients and the best therapeutic options for those with cancer-associated myositis. In this chapter, we will review the current knowledge regarding the epidemiology, risk factors, association with specific autoantibodies, diagnosis, and management of cancer-associated myositis (CAM).

Purpose of Review Positron emission tomography (PET) combined with computed tomography (CT) has proven useful as a cancer screening technique in patients with inflammatory myopathy, mainly dermatomyositis. In this review, we focus on advances in this direction and other potential applications of PET/CT in patients with inflammatory myopathy. Recent Findings Cancer screening by PET/CT seems suitable and cost-effective in patients with myositis. It has also shown value as a hybrid technique for diagnosing myositis versus controls and could be of interest for differentiating between polymyositis and sporadic inclusion body myositis. Quantification of muscle activity by PET/CT seems reliable. Preliminary data suggest that it could also be used to diagnose and measure the activity of the disease in the lung. Summary PET/CT should be in the toolbox of physicians managing patients with myositis. The multiple applications of PET/CT include its value for cancer screening, measuring the activity of the disease in muscle, and helping to differentiate between myositis phenotypes. The possibility to diagnose and monitor inflammatory lung activity remains to be demonstrated in welldesigned studies.

ObjectivesMyositis is a heterogeneous family of diseases that includes dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM), inclusion body myositis (IBM), polymyositis and overlap myositis. Additional subtypes of myositis can be defined by the presence of myositis-specific autoantibodies (MSAs). The purpose of this study was to define unique gene expression profiles in muscle biopsies from patients with MSA-positive DM, AS and IMNM as well as IBM.MethodsRNA-seq was performed on muscle biopsies from 119 myositis patients with IBM or defined MSAs and 20 controls. Machine learning algorithms were trained on transcriptomic data and recursive feature elimination was used to determine which genes were most useful for classifying muscle biopsies into each type and MSA-defined subtype of myositis.ResultsThe support vector machine learning algorithm classified the muscle biopsies with >90% accuracy. Recursive feature elimination identified genes that are most useful to the machine learning algorithm and that are only overexpressed in one type of myositis. For example, CAMK1G (calcium/calmodulin-dependent protein kinase IG), EGR4 (early growth response protein 4) and CXCL8 (interleukin 8) are highly expressed in AS but not in DM or other types of myositis. Using the same computational approach, we also identified genes that are uniquely overexpressed in different MSA-defined subtypes. These included apolipoprotein A4 (APOA4), which is only expressed in anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) myopathy, and MADCAM1 (mucosal vascular addressin cell adhesion molecule 1), which is only expressed in anti-Mi2-positive DM.ConclusionsUnique gene expression profiles in muscle biopsies from patients with MSA-defined subtypes of myositis and IBM suggest that different pathological mechanisms underly muscle damage in each of these diseases.

Objectives. To analyse the influence of genetic alterations and differential expression of transcription intermediary factor 1 (TIF1) genes in the pathophysiology of cancer-associated myositis (CAM). Methods. Paired blood and tumour DNA samples from patients with anti-TIF1 gamma-positive CAM and from controls were analysed by whole-exome sequencing for the presence of somatic mutations and loss of heterozygosity (LOH) in their TIF1 genes. The genesis and maintenance of the autoimmune process were investigated immunohistochemically by studying TIF1 gamma expression in the different tissues involved in CAM (skin, muscle and tumour) based on the immunohistochemical H-score. Results. From seven patients with anti-TIF1 gamma-positive CAM, we detected one somatic mutation and five cases of LOH in one or more of the four TIF1 genes compared with just one case of LOH in tumours from TIF1 gamma-negative myositis patients (86% vs 17%; P = 0.03). Compared with type-matched control tumours from non-myositis patients, TIF1 gamma staining was more intense in tumours from anti-TIF1 gamma-positive patients (H-score 255 vs 196;P = 0.01). Also, TIF1 gamma staining in muscle was slightly more intense in anti-TIF1 gamma-positive than in anti-TIF1 gamma-negative myositis (H-score 22 vs 5; P = 0.03). In contrast, intense TIF1 gamma staining was detected in the skin of both myositis and control patients. Conclusion. Tumours from paraneoplastic anti-TIF1 gamma-positive patients showed an increased number of genetic alterations, such as mutations and LOH, in TIF1 genes. These genetic alterations, in the context of a high expression of TIF1 gamma in the tumour, muscle and skin of these patients may be key to understanding the genesis of paraneoplastic myositis.

Background:There is a well-recognized association between cancer and myositis, so cancer screening at diagnosis is recommended.Objectives:We aim to report the results of our cancer screening strategy and to ascertain the reliability of using PET/CT to identify cancer-associated myositis (CAM) in a large cohort of patients with myositis from a single center over 10 years.Methods:This retrospective observational study included all patients diagnosed with any type of myositis except for inclusion body myositis. Cancer screening strategy was individualized according to clinical and serological data, including PET/CT as the main test to detect occult cancer (OC). Procedures derived from a positive PET/CT were registered. Qualitative data expressed as percentages, and quantitative data as the median with the interquartile range were analyzed. A ROC curve was used to estimate the reliability of PET/CT for CAM diagnosis.Results:Seventy-seven out of 131 patients underwent a PET/CT for OC screening. The performance of the PET/CT in patients with myositis at disease onset yielded an area under the curve ROC of 0.87 (0.73-0.97) for CAM diagnosis. Invasive procedures in 7 (9%) patients without a final diagnosis of cancer did not cause derived complications. Patients not evaluated for OC did not develop cancer after a median follow-up of 3.3 years (1.7-6.7).Conclusion:Cancer screening strategy should be individualized. PET/CT at myositis onset seems to be an efficient approach to rule out CAM. This practice does not seem to significantly increase harm to patients related to the additional tests needed to clarify inconclusive results.Disclosure of Interests:None declared

Background:Several reports have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may trigger a vigorous immune response that could lead to the appearance of various autoantibodies such as antinuclear antibodies, antiphospholipid antibodies or anti-neutrophil cytoplasmic antibodies, among others. Moreover, the pulmonary involvement in SARS-CoV-2 may resemble that of patients with anti-MDA5 positive syndrome or acute form of antisynthetase syndrome.Objectives:Our aim was to analyse the presence of anti-MDA5 and other myositis-specific autoantibodies such as the antisynthetase antibodies in patients diagnosed with severe acute respiratory syndrome caused by SARS-CoV-2.Methods:Retrospective observational study performed in a tertiary care center. We included 28 patients admitted to the intensive care unit with severe acute respiratory syndrome, 14 at the onset of the disease (group A) and 14 after 30 days of being treated in an intensive care unit (group B). Chest CT was performed at the admission. We analyzed the presence of anti-MDA5 and antisynthetase antibodies by immunoblot (Euroimmune®) and in those who were positive we performed a confirmatory test by immunoprecipitation.Results:All chest CT showed bilateral ground glass pattern. Three out of 14 patients of group A (12 males, 86%, mean ± SD age 67.1 ± 12.2) were positive for antisynthetase antibodies (2 anti-PL7, 1 anti-Jo1), and 6 out of 14 patients of the group B (6 males, 48%, mean ± SD age 68.7 ± 8.1) were positive to antisynthetase antibodies (2 anti-PL7, 2 anti-PL-12, 1 anti-EJ, 1 anti-OJ+PL7). Immunoblots also show positivity for other myositis-specific or associated antibodies, such as anti-TIF1g, anti-PM75, anti-SAE and anti-SRP. All of these results found by immunoblotting were negative by immunoprecipitation. None of the 28 patients were positive for anti-MDA5 antibodies.Conclusion:Severe SARS-CoV-2 pneumonia is characterized by ground glass pattern in chest CT, as it is found in anti-MDA5 or antisynthetase syndrome. The positivity of several myositis related autoantibodies showed in immunoblot appears to be more related to the vigorous immune response producing polyclonal immunoglobulins than triggering a real myositis-associated interstitial lung disease. Clinicians must be aware about these false positive results in patients with severe COVID-19 acute respiratory syndrome.References:[1]Xu Q. MDA5 should be detected in severe COVID-19 patients. Med Hypotheses. 2020; 143:109890.[2]Giannini M, Ohana M, Nespola B, Zanframundo G, Geny B, Meyer A. Similarities between COVID-19 and anti-MDA5 syndrome: what can we learn for better care? Eur Respir J. 2020; 56:2001618.[3]Vlachoyiannopoulos PG, Magira E, Alexopoulos H, Jahaj E, Theophilopoulou K, Kotanidou A, Tzioufas AG. Autoantibodies related to systemic autoimmune rheumatic diseases in severely ill patients with COVID-19. Ann Rheum Dis. 2020 Dec;79(12):1661-1663Disclosure of Interests:None declared