Not all COVID-19 pandemic waves are alike

Objective: We aimed to assess differences in patients' profiles in the first two surges of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in Barcelona, Spain. Methods: We prospectively collected data from all adult patients with SARS-CoV-2 infection diagnosed at the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. All the patients were diagnosed through nasopharyngeal swab PCR. The first surge spanned from 1st March to 13th August 2020, while surge two spanned from 14th August to 8th December 2020. Results: There were 2479 and 852 patients with microbiologically proven SARS-CoV-2 infection in surges one and two, respectively. Patients from surge two were significantly younger (median age 52 (IQR 35) versus 59 (40) years, respectively, p < 0.001), had fewer comorbidities (379/852, 44.5% versus 1237/2479, 49.9%, p 0.007), and there was a shorter interval between onset of symptoms and diagnosis (median 3 (5) versus 4 (5) days, p < 0.001). All-cause in-hospital mortality significantly decreased for both the whole population (24/852, 2.8% versus 218/2479, 8.8%, p < 0.001) and hospitalized patients (20/302, 6.6% versus 206/1570, 13.1%, p 0.012). At adjusted logistic regression analysis, predictors of in-hospital mortality were older age (per year, adjusted odds ratio (aOR) 1.079, 95%CI 1.063-1.094), male sex (aOR 1.476, 95%CI 1.079-2.018), having comorbidities (aOR 1.414, 95%CI 0.934-2.141), ICU admission (aOR 3.812, 95%CI 1.875-7.751), mechanical ventilation (aOR 2.076, 95%CI 0.968-4.454), and coronavirus disease 2019 (COVID-19) during surge one (with respect to surge two) (aOR 2.176, 95%CI 1.286-3.680). Conclusions: First-wave SARS-CoV-2-infected patients had a more than two-fold higher in-hospital mortality than second-wave patients. The causes are likely multifactorial

The added value of 18f-FDG PET/CT in the assessment of onset and steroid resistant polimyalgia rheumatica

PMR is a common inflammatory rheumatic disease. Although its clinical characteristics are fully recognized, no specific test for its diagnosis has been established to date. Several studies have described a wide variety of diseases that present with polymyalgic symptoms. A 18FDG-PET/CT scan could help to deal with these differential diagnoses. The goal of our study is to describe the findings of the 18FDG-PET/CT scan in a cohort of PMR patients and to detail how the 18FDG-PET/CT scan improves accuracy when diagnosing other underlying conditions. This cross-sectional study enrolled patients with a diagnosis of PMR who underwent to a 18FDG-PET/CT scan to rule out other diagnosis. The 18FDG-PET/CT scan was performed either following clinical criteria at the onset of clinical symptoms or when the patient became PMR steroid resistant. Patients' demographic, clinical and analytical data at the moment of the 18FDG-PET/CT scan were recorded. The final diagnosis was confirmed according to clinical judgement. A total of 103 patients with PMR were included. In 49.51% of patients, the 18FDG-PET/CT scan was ordered to study resistance to steroid therapy. The final diagnoses of patients were PMR in 70.9% patients, large vessel vasculitis in 15.5%, neoplasms 4.8% and another diagnosis in the rest. The 18FDG-PET/CT scan is a very useful technique for the study of Polymyalgia Rheumatica, not only to help in the diagnostic process, but also due to its role in the identification of a variety of PMR-like patrons

Management of progressive pulmonary fibrosis associated with connective tissue disease

Altres ajuts: Roche; Boehringer Ingelheim; Pfizer.Introduction: Fibrotic interstitial lung disease (ILD) is a frequent and severe complication of connective tissue disease (CTD). Areas covered: In this narrative review, we update the most relevant differential characteristics of fibrotic ILD associated with CTD (CTD-ILD) and propose a diagnostic and therapeutic approach based on a review of the articles published between 2002 and 2022 through PubMed. Expert opinion: The subset of ILD, mainly the radiological/histological pattern and the degree of fibrotic component, usually determines the prognosis and therapeutic strategy for these patients. Some patients with CTD-ILD can develop progressive pulmonary fibrosis (PPF) with severe deterioration of lung function, rapid progression to chronic respiratory failure, and high mortality. PPF has been described in many CTDs, mainly in systemic sclerosis and rheumatoid arthritis, and requires a multidisciplinary diagnostic and therapeutic approach to improve patient outcomes

Growth differentiation factor 15 (Gdf-15) : A novel biomarker associated with poorer respiratory function in covid-19

It is essential to find new biomarkers for severity stratification of patients with coronavirus disease (COVID-19). Growth differentiation factor 15 (GDF-15) is upregulated in pathological conditions that involve inflammation and/or oxidative stress. We determined circulating levels of GDF-15 and correlated them with clinical and laboratory parameters reflecting severity in 84 patients with COVID-19, finding that GDF-15 levels were higher in both patients than in 20 healthy controls and were higher in patients with poorer respiratory function. GDF-15 levels also correlated with interleukin-6, C-reactive protein, ferritin and D-dimer levels and with neutrophilia and lymphopenia. Of all the analysed biomarkers, GDF-15 showed the best area under the receiver operating characteristics curve in identifying patients with poor respiratory function. In conclusion, our data support GDF-15 as a biomarker associated with pulmonary impairment in COVID-19 and so can potentially be useful in stratifying COVID-19 cases by severity

Pulmonary Thrombosis or Embolism in a Large Cohort of Hospitalized Patients With Covid-19

Objective: We set out to analyze the incidence and predictive factors of pulmonary embolism (PE) in hospitalized patients with Covid-19. Methods: We prospectively collected data from all consecutive patients with laboratory-confirmed Covid-19 admitted to the Hospital de la Santa Creu i Sant Pau, a university hospital in Barcelona, between March 9 and April 15, 2020. Patients with suspected PE, according to standardized guidelines, underwent CT pulmonary angiography (CTPA). Results: A total of 1,275 patients with Covid-19 were admitted to hospital. CTPA was performed on 76 inpatients, and a diagnosis of PE was made in 32 (2.6% [95%CI 1.7-3.5%]). Patients with PE were older, and they exhibited lower PaO:FiO ratios and higher levels of D-dimer and C-reactive protein (CRP). They more often required admission to ICU and mechanical ventilation, and they often had longer hospital stays, although in-hospital mortality was no greater than in patients without PE. High CRP and D-dimer levels at admission (≥150 mg/L and ≥1,000 ng/ml, respectively) and a peak D-dimer ≥6,000 ng/ml during hospital stay were independent factors associated with PE. Prophylactic low molecular weight heparin did not appear to prevent PE. Increased CRP levels correlated with increased D-dimer levels and both correlated with a lower PaO:FiO. Conclusions: The 2.6% incidence of PE in Covid-19 hospitalized patients is clearly high. Higher doses of thromboprophylaxis may be required to prevent PE, particularly in patients at increased risk, such as those with high levels of CRP and D-dimer at admission. These findings should be validated in future studies

Krebs von den Lungen-6 glycoprotein circulating levels are not useful as prognostic marker in COVID-19 pneumonia : A large prospective cohort study

Altres ajuts: Departament de Salut, Generalitat de Catalunya (COVID-PoC BioCAT).Coronavirus disease 2019 (COVID-19) has rapidly expanded worldwide. Currently, there are no biomarkers to predict respiratory worsening in patients with mild to moderate COVID-19 pneumonia. Small studies explored the use of Krebs von de Lungen-6 circulating serum levels (sKL-6) as a prognostic biomarker of the worsening of COVID-19 pneumonia. We aimed at a large study to determine the prognostic value of sKL-6 in predicting evolving trends in COVID-19. We prospectively analyzed the characteristics of 836 patients with COVID-19 with mild lung disease on admission. sKL-6 was obtained in all patients at least at baseline and compared among patients with or without respiratory worsening. The receiver operating characteristic curve was used to find the optimal cutoff level. A total of 159 (19%) patients developed respiratory worsening during hospitalization. Baseline sKL-6 levels were not higher in patients who had respiratory worsening (median {IQR} 315.5 {209-469} vs. 306 {214-423} U/ml p = 0.38). The last sKL-6 and the change between baseline and last sKL-6 were higher in the respiratory worsening group (p = 0.02 and p < 0.0001, respectively). The best sKL-6 cutoff point for respiratory worsening was 497 U/ml (area under the curve 0.52; 23% sensitivity and 85% specificity). sKL-6 was not found to be an independent predictor of respiratory worsening. A conditional inference tree (CTREE) was not useful to discriminate patients at risk of worsening. We found that sKL-6 had a low sensibility to predict respiratory worsening in patients with mild-moderate COVID-19 pneumonia and may not be of use to assess the risk of present respiratory worsening in inpatients with COVID-19 pneumonia

Thrombospondin-1 mediates muscle damage in brachio-cervical inflammatory myopathy and systemic sclerosis

To describe the clinical, serologic and histologic features of a cohort of patients with brachio-cervical inflammatory myopathy (BCIM) associated with systemic sclerosis (SSc) and unravel disease-specific pathophysiologic mechanisms occurring in these patients. We reviewed clinical, immunologic, muscle MRI, nailfold videocapillaroscopy, muscle biopsy, and response to treatment data from 8 patients with BCIM-SSc. We compared cytokine profiles between patients with BCIM-SSc and SSc without muscle involvement and controls. We analyzed the effect of the deregulated cytokines in vitro (fibroblasts, endothelial cells, and muscle cells) and in vivo. All patients with BCIM-SSc presented with muscle weakness involving cervical and proximal muscles of the upper limbs plus Raynaud syndrome, telangiectasia and/or sclerodactilia, hypotonia of the esophagus, and interstitial lung disease. Immunosuppressive treatment stopped the progression of the disease. Muscle biopsy showed pathologic changes including the presence of necrotic fibers, fibrosis, and reduced capillary number and size. Cytokines involved in inflammation, angiogenesis, and fibrosis were deregulated. Thrombospondin-1 (TSP-1), which participates in all these 3 processes, was upregulated in patients with BCIM-SSc. In vitro, TSP-1 and serum of patients with BCIM-SSc promoted proliferation and upregulation of collagen, fibronectin, and transforming growth factor beta in fibroblasts. TSP-1 disrupted vascular network, decreased muscle differentiation, and promoted hypotrophic myotubes. In vivo, TSP-1 increased fibrotic tissue and profibrotic macrophage infiltration in the muscle. Patients with SSc may present with a clinically and pathologically distinct myopathy. A prompt and correct diagnosis has important implications for treatment. Finally, TSP-1 may participate in the pathologic changes observed in muscle

Gene-level association analysis of systemic sclerosis: A comparison of African-Americans and White populations

All authors: Olga Y. Gorlova , Yafang Li, Ivan Gorlov, Jun Ying, Wei V. Chen, Shervin Assassi, John D. Reveille, Frank C. Arnett, Xiaodong Zhou, Lara Bossini-Castillo, Elena Lopez-Isac, Marialbert Acosta-Herrera, Peter K. Gregersen, Annette T. Lee, Virginia D. Steen, Barri J. Fessler, Dinesh Khanna, Elena Schiopu, Richard M. Silver, Jerry A. Molitor, Daniel E. Furst, Suzanne Kafaja, Robert W. Simms, Robert A. Lafyatis, Patricia Carreira, Carmen Pilar Simeon, Ivan Castellvi, Emma Beltran, Norberto Ortego, Christopher I. Amos, Javier Martin, Maureen D. Mayes.Data Availability Statement: Genetic data is available from dbGaP repository (https://www.ncbi. nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_ id=phs000357.v1.p1).Gene-level analysis of ImmunoChip or genome-wide association studies (GWAS) data has not been previously reported for systemic sclerosis (SSc, scleroderma). The objective of this study was to analyze genetic susceptibility loci in SSc at the gene level and to determine if the detected associations were shared in African-American and White populations, using data from ImmunoChip and GWAS genotyping studies. The White sample included 1833 cases and 3466 controls (956 cases and 2741 controls from the US and 877 cases and 725 controls from Spain) and the African American sample, 291 cases and 260 controls. In both Whites and African Americans, we performed a gene-level analysis that integrates association statistics in a gene possibly harboring multiple SNPs with weak effect on disease risk, using Versatile Gene-based Association Study (VEGAS) software. The SNP-level analysis was performed using PLINK v.1.07. We identified 4 novel candidate genes (STAT1, FCGR2C, NIPSNAP3B, and SCT) significantly associated and 4 genes (SERBP1, PINX1, TMEM175 and EXOC2) suggestively associated with SSc in the gene level analysis in White patients. As an exploratory analysis we compared the results on Whites with those from African Americans. Of previously established susceptibility genes identified in Whites, only TNFAIP3 was significant at the nominal level (p = 6.13x10-3) in African Americans in the gene-level analysis of the ImmunoChip data. Among the top suggestive novel genes identified in Whites based on the ImmunoChip data, FCGR2C and PINX1 were only nominally significant in African Americans (p = 0.016 and p = 0.028, respectively), while among the top novel genes identified in the gene-level analysis in African Americans, UNC5C (p = 5.57x10-4) and CLEC16A (p = 0.0463) were also nominally significant in Whites. We also present the gene-level analysis of SSc clinical and autoantibody phenotypes among Whites. Our findings need to be validated by independent studies, particularly due to the limited sample size of African Americans.Funding was provided to MDM by the National Institutes of Health (NIH) the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS https://www.niams.nih.gov/) Centers of Research Translation (CORT) P50-AR054144, NIH grant N01-AR-02251 and R01-AR-055258, and the Department of Defense (DD) Congressionally Directed Medical Research Program (http://cdmrp.army.mil/) W81XWH-07-1-011 and WX81XWH-13-1-0452 for the collection, analysis and interpretation of the data

Effectiveness and safety of tocilizumab in patients with systemic sclerosis : a propensity score matched controlled observational study of the EUSTAR cohort

Objectives Tocilizumab showed trends for improving skin fibrosis and prevented progression of lung fibrosis in systemic sclerosis (SSc) in randomised controlled clinical trials. We aimed to assess safety and effectiveness of tocilizumab in a real-life setting using the European Scleroderma Trial and Research (EUSTAR) database. Methods Patients with SSc fulfilling the American College of Rheumatology (ACR)/EULAR 2013 classification criteria, with baseline and follow-up visits at 12±3 months, receiving tocilizumab or standard of care as the control group, were selected. Propensity score matching was applied. Primary endpoints were the modified Rodnan skin score (mRSS) and FVC at 12±3 months compared between the groups. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months. Results Ninety-three patients with SSc treated with tocilizumab and 3180 patients with SSc with standard of care fulfilled the inclusion criteria. Comparison between groups did not show significant differences, but favoured tocilizumab across all predefined primary and secondary endpoints: mRSS was lower in the tocilizumab group (difference -1.0, 95% CI -3.7 to 1.8, p=0.48). Similarly, FVC % predicted was higher in the tocilizumab group (difference 1.5 (-6.1 to 9.1), p=0.70). The percentage of progressive/regressive patients favoured tocilizumab over controls. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles. Conclusion Although this large, observational, controlled, real-life EUSTAR study did not show significant effectiveness of tocilizumab on skin and lung fibrosis, the consistency of direction of all predefined endpoints generates hypothesis for potential effectiveness in a broader SSc population

GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments