Background: Cardiac troponin (cTn) T and cTnI are considered cardiac specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a noncardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMDs). Methods: We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in 4 hospitals in 2 countries. After a cardiac workup, patients were adjudicated into 3 predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed with high-sensitivity (hs-) cTnT (hs-cTnT–Elecsys) and 3 hs-cTnI assays (hs-cTnI–Architect, hs-cTnI–Access, hs-cTnI–Vista) and compared with those of control subjects without SMD presenting with adjudicated noncardiac chest pain to the emergency department (n=3508; mean age, 55 years; 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared with biopsies obtained in control subjects without SMD. Results: Among 211 patients (mean age, 57 years; 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) to having mild disease, and 59 (28%) to having severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no to those with mild and severe cardiac disease for all assays (all P <0.001). hs-cTnT–Elecsys concentrations were significantly higher in patients with SMD versus control subjects (median, 16 ng/L [interquartile range (IQR), 7–32.5 ng/L] versus 5 ng/L [IQR, 3–9 ng/L]; P <0.001), whereas hs-cTnI concentrations were mostly similar (hs-cTnI–Architect, 2.5 ng/L [IQR, 1.2–6.2 ng/L] versus 2.9 ng/L [IQR, 1.8–5.0 ng/L]; hs-cTnI–Access, 3.3 ng/L [IQR, 2.4–6.1 ng/L] versus 2.7 ng/L [IQR, 1.6–5.0 ng/L]; and hs-cTnI–Vista, 7.4 ng/L [IQR, 5.2–13.4 ng/L] versus 7.5 ng/L [IQR, 6–10 ng/L]). hs-cTnT–Elecsys concentrations were above the upper limit of normal in 55% of patients with SMD versus 13% of control subjects ( P <0.01). mRNA analyses in skeletal muscle biopsies (n=33), mostly (n=24) from individuals with noninflammatory myopathy and myositis, showed 8-fold upregulation of TNNT2 , encoding cTnT (but none for TNNI3 , encoding cTnI) versus control subjects (n=16, P _Wald <0.001); the expression correlated with pathological disease activity ( R =0.59, P _t-statistic <0.001) and circulating hs-cTnT concentrations ( R =0.26, P _t-statistic =0.031). Conclusions: In patients with active chronic SMD, elevations in cTnT concentrations are common and not attributable to cardiac disease in the majority. This was not observed for cTnI and may be explained in part by re-expression of cTnT in skeletal muscle. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03660969.

COVID-19 in a patient with systemic sclerosis treated with tocilizumab for SSc-ILD During the current global outbreak of coronavirus disease 2019 (COVID-19), risk stratification of patients is of utmost importance. Currently, patients >65 years and those with pre-existing medical conditions such as cardiovascular disease, chronic respiratory disease or diabetes mellitus are considered at higher risk for severe disease. 1 The Swiss Federal Office of Public Health, like similar authorities around the world, has additionally included patients on immunosuppressants in the high-risk group for developing severe COVID-19. 2 However, at this moment we do not have enough evidence either to support or to reject this assumption. We report the case of a 57-year-old woman with systemic sclerosis (SSc) who developed COVID-19. Comorbidities were insulindependent type 2 diabetes mellitus and WHO grade I obesity. The anti-topoisomerase I antibody-positive patient was diagnosed with SSc in 2017. SSc-associated interstitial lung disease (SSc-ILD), with cough and exertion dyspnoea, was the leading organ manifestation, associated with symmetrical, non-erosive polyarthritis, and elevated acute phase reactants. Treatment with the anti-interleukin (IL) 6 receptor blocker tocilizumab, with 8 mg/kg body weight every 4 weeks intravenously, was started, leading to a good control of both arthritis and SSc-ILD, with gradual improvement of musculoskeletal and respiratory symptoms, lung function and highresolution CT imaging (figure 1). At the last annual assessment in January 2020, her forced vital capacity and carbon monoxide lung diffusion capacity were 92% and 70% of the respective predicted values. Tocilizumab was continued at 5-week intervals. On 12 March 2020, 4 weeks after the last tocilizumab infusion, the patient presented to our hospital's emergency department with cough, headache and general malaise since about 1 week. She reported contact with a patient with COVID-19 2 weeks earlier. As she was in relatively good general health condition, subfebrile (37.6°C), with unchanged bibasal lung crackles and no significant dyspnoea, she was allowed to return home with symptomatic treatment only. The nasopharyngeal swab was positive for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) by realtime reverse transcription-PCR. She was quarantined at home and monitored by daily telephone calls, and the upcoming tocilizumab infusion was postponed. The symptoms remained mild, and, 10 days later, she reported to be free of symptoms. A follow-up nasopharyngeal swab for SARS-Cov2 performed on March 26 turned out negative. She was thus declared cured from the infection and scheduled to receive the next tocilizumab dose 4 days after the negative test.

Background Radiomic features calculated from routine medical images show great potential for personalised medicine in cancer. Patients with systemic sclerosis (SSc), a rare, multiorgan autoimmune disorder, have a similarly poor prognosis due to interstitial lung disease (ILD). Here, our objectives were to explore computed tomography (CT)-based high-dimensional image analysis (“radiomics”) for disease characterisation, risk stratification and relaying information on lung pathophysiology in SSc-ILD. Methods We investigated two independent, prospectively followed SSc-ILD cohorts (Zurich, derivation cohort, n=90; Oslo, validation cohort, n=66). For every subject, we defined 1355 robust radiomic features from standard-of-care CT images. We performed unsupervised clustering to identify and characterise imaging-based patient clusters. A clinically applicable prognostic quantitative radiomic risk score (qRISSc) for progression-free survival (PFS) was derived from radiomic profiles using supervised analysis. The biological basis of qRISSc was assessed in a cross-species approach by correlation with lung proteomic, histological and gene expression data derived from mice with bleomycin-induced lung fibrosis. Results Radiomic profiling identified two clinically and prognostically distinct SSc-ILD patient clusters. To evaluate the clinical applicability, we derived and externally validated a binary, quantitative radiomic risk score (qRISSc) composed of 26 features that accurately predicted PFS and significantly improved upon clinical risk stratification parameters in multivariable Cox regression analyses in the pooled cohorts. A high qRISSc score, which identifies patients at risk for progression, was reverse translatable from human to experimental ILD and correlated with fibrotic pathway activation. Conclusions Radiomics-based risk stratification using routine CT images provides complementary phenotypic, clinical and prognostic information significantly impacting clinical decision making in SSc-ILD.

Background: Interstitial lung disease (ILD) is a frequent manifestation of connective tissue diseases (CTDs) and is associated with high morbidity and mortality. Clinical practice guidelines to standardise screening, diagnosis, treatment and follow-up for CTD-ILD are of high importance for optimised patient care. Methods: A European Respiratory Society and European Alliance of Associations for Rheumatology task force committee, composed of pulmonologists, rheumatologists, pathologists, radiologists, methodologists and patient representatives, developed recommendations based on PICO (Patients, Intervention, Comparison, Outcomes) questions with grading of the evidence according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology and complementary narrative questions agreed on by both societies. For both PICO and narrative questions, the Evidence to Decision framework was used to formulate the recommendations. Results: The task force committee concluded with recommendations for 25 PICO and 28 narrative questions, regarding ILD in the context of systemic sclerosis, rheumatoid arthritis (RA), idiopathic inflammatory myopathies, Sjögren disease (SjD), systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). In four narrative questions, regarding screening and assessment of risk for ILD progression in MCTD, SjD and SLE and one PICO question regarding pirfenidone in CTD-ILD other than RA-ILD, the task force had insufficient evidence to support recommendations. Screening, diagnostic, monitoring and treatment algorithms were developed based on the recommendations and usual clinical practice. Conclusions: We provide practical guidance by evidence-based recommendations to clinicians for each of the CTDs. In many cases there is low certainty or absence of evidence and we encourage further research to fill these gaps.

TGF-β is a master regulator of fibrosis, driving the differentiation of fibroblasts into apoptosis-resistant myofibroblasts and sustaining the production of extracellular matrix (ECM) components. Here, we identified the nuclear long noncoding RNA (lncRNA) H19X as a master regulator of TGF-β–driven tissue fibrosis. H19X was consistently upregulated in a wide variety of human fibrotic tissues and diseases and was strongly induced by TGF-β, particularly in fibroblasts and fibroblast-related cells. Functional experiments following H19X silencing revealed that H19X was an obligatory factor for TGF-β–induced ECM synthesis as well as differentiation and survival of ECM-producing myofibroblasts. We showed that H19X regulates DDIT4L gene expression, specifically interacting with a region upstream of the DDIT4L gene and changing the chromatin accessibility of a DDIT4L enhancer. These events resulted in transcriptional repression of DDIT4L and, in turn, in increased collagen expression and fibrosis. Our results shed light on key effectors of TGF-β–induced ECM remodeling and fibrosis.

Background Immune responses on SARS-CoV-2 vaccination in patients receiving anti-CD20 therapies are impaired but vary considerably. We conducted a systematic review and meta-analysis of the literature on SARS-CoV-2 vaccine induced humoral and cell-mediated immune response in patients previously treated with anti-CD20 antibodies. Methods We searched PubMed, Embase, Medrxiv and SSRN using variations of search terms ‘anti-CD20’, ‘vaccine’ and ‘COVID’ and included original studies up to 21 August 2021. We excluded studies with missing data on humoral or cell-mediated immune response, unspecified methodology of response testing, unspecified timeframes between vaccination and blood sampling or low number of participants (≤3). We excluded individual patients with prior COVID-19 or incomplete vaccine courses. Primary endpoints were humoral and cell-mediated immune response rates. Subgroup analyses included time since anti-CD20 therapy, B cell depletion and indication for anti-CD20 therapy. We used random-effects models of proportions. Findings Ninety studies were assessed. Inclusion criteria were met by 23 studies comprising 1342 patients. Overall rate of humoral response was 0.40 (95% CI 0.35 to 0.47). Overall rate of cell-mediated immune responses was 0.71 (95% CI 0.57 to 0.87). A time interval >6 months since last anti-CD20 therapy was associated with higher humoral response rates with 0.63 (95% CI 0.53 to 0.72) versus <6 months 0.2 (95% CI 0.03 to 0.43); p=0<01. Similarly, patients with circulating B cells more frequently showed humoral responses. Anti-CD20-treated kidney transplant recipients showed lower humoral response rates than patients with haematological malignancies or autoimmune disease. Interpretation Patients on anti-CD20 therapies can develop humoral and cell-mediated immune responses after SARS-CoV-2 vaccination, but subgroups such as kidney transplant recipients or those with very recent therapy and depleted B cell are at high risk for non-seroconversion and should be individually assessed for personalised SARS-CoV-2 vaccination strategies. Potential limitations are small patient numbers and heterogeneity of studies included. Funding This study was funded by Bern University Hospital.