Subcutaneous Sarilumab in hospitalised patients with moderate-severe COVID-19 infection compared to the standard of care (SARCOVID): a structured summary of a study protocol for a randomised controlled trial

The main aim of the study is to evaluate the efficacy of a single dose of sarilumab, in subcutaneous administration, in hospitalised patients with moderate to early severe COVID-19 infection compared to the current standard of care, to prevent progression to systemic hyperinflammatory status. Our hypothesis is that use of subcutaneous sarilumab in early stages (window of opportunity) of COVID-19 moderate-severe pneumonia can prevent higher oxygenation requirements through non-invasive and invasive mechanical ventilation and decrease in-hospital stays, as well as death rate. The secondary objectives of the study are to evaluate the safety of sarilumab through hospitalisation and up to day 14 after discharge, compared to the control arm as assessed by incidence of serious and non serious adverse events (SAEs). In addition, as an exploratory objective, to compare the baseline clinical and biological parameters, including serum IL-6 levels, of the intervention population against controls of the same pandemic outbreak (using a propensity score) to search for markers that identify the best candidates for the treatment with subcutaneous IL-6R inhibitors and to attempt an approximation in the temporal frame of the “window of opportunity”Sanofi provides medication for the intervention arm sarilumab (Kevzara, 40 prefilled syringes

Interleukin-15 and interferon-gamma participate in the cross-talk between natural killer and monocytic cells required for tumour necrosis factor production.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.We have characterized the lymphocyte subset and the receptor molecules involved in inducing the secretion of TNF by monocytic cells in vitro. The TNF secreted by monocytic cells was measured when they were co-cultured with either resting or IL-15-stimulated lymphocytes, T cells, B cells or natural killer (NK) cells isolated from the peripheral blood of healthy subjects and from the synovial fluid from patients with inflammatory arthropathies. Co-culture with IL-15-activated peripheral blood or synovial fluid lymphocytes induced TNF production by monocytic cells within 24 hours, an effect that was mainly mediated by NK cells. In turn, monocytic cells induced CD69 expression and IFN-gamma production in NK cells, an effect that was mediated mainly by beta2 integrins and membrane-bound IL-15. Furthermore, IFN-gamma increased the production of membrane-bound IL-15 in monocytic cells. Blockade of beta2 integrins and membrane-bound IL-15 inhibited TNF production, whereas TNF synthesis increased in the presence of anti-CD48 and anti-CD244 (2B4) monoclonal antibodies. All these findings suggest that the cross-talk between NK cells and monocytes results in the sustained stimulation of TNF production. This phenomenon might be important in the pathogenesis of conditions such as rheumatoid arthritis in which the synthesis of TNF is enhanced

Experience with the use of Rituximab for the treatment of rheumatoid arthritis in a tertiary Hospital in Spain: RITAR study

There is evidence supporting that there are no relevant clinical differences between dosing rituximab 1000 mg or 2000 mg per cycle in rheumatoid arthritis (RA) patients in clinical trials, and low-dose cycles seem to have a better safety profile. Our objective was to describe the pattern of use of rituximab in real-life practice conditions. Methods: Rituximab for RA in clinical practice (RITAR) study is a retrospective cohort study from 2005 to 2015. Eligibility criteria were RA adults treated with rituximab for active articular disease. Response duration was the main outcome defined as months elapsed from the date of rituximab first infusion to the date of flare. A multivariable analysis was performed to determine the variables associated with response duration. Results: A total of 114 patients and 409 cycles were described, 93.0% seropositive and 80.7% women. Rituximab was mainly used as second-line biological therapy. On demand retreatment was used in 94.6% of cases versus fixed 6 months retreatment in 5.4%. Median response duration to on demand rituximab cycles was 10 months (interquartile range, 7–13). Multivariable analysis showed that age older than 65 years, number of rituximab cycles, seropositivity, and first- or second-line therapy were associated with longer response duration. The dose administered at each cycle was not significantly associated with response duration. Conclusions: Our experience suggests that 1000 mg rituximab single infusion on demand is a reasonable schedule for long-term treatment of those patients with good response after the first cycles, especially in seropositive patients and when it is applied as a first- or second-line biological therap

Improved RA classification among early arthritis patients with the concordant presence of three RA autoantibodies: Analysis in two early arthritis clinics

Background: The patients with RA benefit from early identification soon after the first clinical symptoms appear. The 2010 ACR/EULAR classification criteria were developed to fulfill this need and their application has been demonstrated to be effective. However, there is still room for improvement. Therefore, we aimed to evaluate the potential of the concordant presence of RF, anti-CCP and anti-carbamylated protein antibodies to improve current RA classification among early arthritis (EA) patients. Methods: Data from the first visit of 1057 patients in two EA prospective cohorts were used. The serological scores from the 2010 ACR/EULAR criteria and the concordant presence of the three RA autoantibodies were assessed relative to a gold standard consisting of the RA classification with the 1987 ACR criteria at the 2 years of follow-up. Results: The concordant presence of three antibodies showed predictive characteristics allowing for direct classification as RA (positive predictive value = 96.1% and OR = 80.9). They were significantly better than the corresponding to the high antibody titers defined as in the 2010 classification criteria (PPV = 88.8%, OR = 26.1). In addition, the concordant presence of two antibodies was also very informative (PPV = 82.3%, OR = 15.1). These results allowed devising a scoring system based only on antibody concordance that displayed similar overall performance as the serological scoring system of the 2010 criteria. However, the best classification was obtained combining the concordance and 2010 serological systems, a combination with a significant contribution from each of the two systems. Discussion: The concordant presence of RA autoantibodies showed an independent contribution to the classification of EA patients that permitted increased discrimination and precision.This work was supported by the Instituto de Salud Carlos III (Spain) through grants [PI17/01606 and RD16/0012/0014 to AG; RD16/0012/0011 to IG-A and RD16/0012/0012 to AB]. These grants are partially financed by the European Regional Development Fund of the EU (FEDER). CR was supported by Ministerio de Educacion Cultura y Deporte (Spain) through a FPU pre-doctoral fellowship [FPU15/03434]. LR-M was supported by a Xunta de Galicia predoctoral contract

Association of acid phosphatase locus 1*C allele with the risk of cardiovascular events in rheumatoid arthritis patients

Introduction: Acid phosphatase locus 1 (ACP1) encodes a low molecular weight phosphotyrosine phosphatase implicated in a number of different biological functions in the cell. The aim of this study was to determine the contribution of ACP1 polymorphisms to susceptibility to rheumatoid arthritis (RA), as well as the potential contribution of these polymorphisms to the increased risk of cardiovascular disease (CV) observed in RA patients. Methods: A set of 1,603 Spanish RA patients and 1,877 healthy controls were included in the study. Information related to the presence/absence of CV events was obtained from 1,284 of these participants. All individuals were genotyped for four ACP1 single-nucleotide polymorphisms (SNPs), rs10167992, rs11553742, rs7576247, and rs3828329, using a predesigned TaqMan SNP genotyping assay. Classical ACP1 alleles (*A, *B and *C) were imputed with SNP data. Results: No association between ACP1 gene polymorphisms and susceptibility to RA was observed. However, when RA patients were stratified according to the presence or absence of CV events, an association between rs11553742*T and CV events was found (P = 0.012, odds ratio (OR) = 2.62 (1.24 to 5.53)). Likewise, the ACP1*C allele showed evidence of association with CV events in patients with RA (P = 0.024, OR = 2.43). Conclusions: Our data show that the ACP1*C allele influences the risk of CV events in patients with R

Validation of galectin‑1 as potential diagnostic biomarker of early rheumatoid arthritis

Galectin 1 (Gal1) is a lectin with a wide cellular expression that functions as a negative regulator of the immune system in several animal models of autoimmune diseases. Identifcation of patients with rheumatoid arthritis (RA) has improved during the last decade, although there is still a need for biomarkers allowing an early diagnosis. In this regard, it has been recently proposed that Gal1 serum levels are increased in patients with RA compared to the general population. However, this topic is controversial in the literature. In this work, we provide additional information about the potential usefulness of Gal1 serum levels as a biomarker for RA diagnosis. We studied Gal1 serum and synovial fuid levels and clinical parameters in samples from 62 patients with early arthritis belonging to the PEARL study. In addition, 24 healthy donors were studied. We found that both patients fulflling RA criteria and patients with undiferentiated arthritis showed higher Gal1 levels than healthy donors. Similar fndings were observed in synovial fuid, which showed even higher levels than serum. However, we did not fnd correlation between Gal1 levels and disease activity or disability. Therefore, our results suggest that Gal1 could be a diagnostic but not a severity biomarker

Brucella ceti infection in dolphins from the Western Mediterranean sea

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A predominant involvement of the triple seropositive patients and others with rheumatoid factor in the association of smoking with rheumatoid arthritis

The major environmental risk factor for rheumatoid arthritis (RA) is smoking, which according to a widely accepted model induces protein citrullination in the lungs, triggering the production of anticitrullinated protein antibodies (ACPA) and RA development. Nevertheless, some research findings do not fit this model. Therefore, we obtained six independent cohorts with 2253 RA patients for a detailed analysis of the association between smoking and RA autoantibodies. Our results showed a predominant association of smoking with the concurrent presence of the three antibodies: rheumatoid factor (RF), ACPA and anti-carbamylated protein antibodies (ACarPA) (3 Ab vs. 0 Ab: OR = 1.99, p = 2.5 × 10?8). Meta-analysis with previous data (4491 patients) confirmed the predominant association with the concurrent presence of the three antibodies (3 Ab vs. 0 Ab: OR = 2.00, p = 4.4 ×10?16) and revealed that smoking was exclusively associated with the presence of RF in patients with one or two antibodies (RF+ 1+2 vs. RF? 0+1+2: OR = 1.32, p = 0.0002). In contrast, no specific association with ACPA or ACarPA was found. Therefore, these results showed the need to understand how smoking favors the concordance of RA specific antibodies and RF triggering, perhaps involving smoking-induced epitope spreading and other hypothesized mechanisms

Interleukin 15 Levels in Serum May Predict a Severe Disease Course in Patients with Early Arthritis

Background: Interleukin-15 (IL-15) is thought to be involved in the physiopathological mechanisms of RA and it can be detected in the serum and the synovial fluid of inflamed joints in patients with RA but not in patients with osteoarthritis or other inflammatory joint diseases. Therefore, the objective of this work is to analyse whether serum IL-15 (sIL-15) levels serve as a biomarker of disease severity in patients with early arthritis (EA). Methodology and Results: Data from 190 patients in an EA register were analysed (77.2% female; median age 53 years; 6-month median disease duration at entry). Clinical and treatment information was recorded systematically, especially the prescription of disease modifying anti-rheumatic drugs. Two multivariate longitudinal analyses were performed with different dependent variables: 1) DAS28 and 2) a variable reflecting intensive treatment. Both included sIL-15 as predictive variable and other variables associated with disease severity, including rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACPA). Of the 171 patients (638 visits analysed) completing the follow-up, 71% suffered rheumatoid arthritis and 29% were considered as undifferentiated arthritis. Elevated sIL-15 was detected in 29% of this population and this biomarker did not overlap extensively with RF or ACPA. High sIL-15 levels (β Coefficient [95% confidence interval]: 0.12 [0.06-0.18]; p&0.001) or ACPA (0.34 [0.01-0.67]; p = 0.044) were significantly and independently associated with a higher DAS28 during follow-up, after adjusting for confounding variables such as gender, age and treatment. In addition, those patients with elevated sIL-15 had a significantly higher risk of receiving intensive treatment (RR 1.78, 95% confidence interval 1.18-2.7; p = 0.007). Conclusions: Patients with EA displaying high baseline sIL-15 suffered a more severe disease and received more intensive treatment. Thus, sIL-15 may be a biomarker for patients that are candidates for early and more intensive treatmentThe work of Belen Díaz-Sánchez was supported by the RETICS Programme (Programa de Redes Temáticas de Investigación Colaborativa [Colaborative Research Thematic Network Programme]; RD08/0075 - RIER [Red de Inflamación y Enfermedades Reumáticas; Inflammation and Rheumatic Diseases Network]) from the Instituto de Salud Carlos III, Spain (URL: www.isciii.es) within the VI National Plan for I+D+I 2008–2011 (FEDER). The work of Isidoro González-Álvaro was in part supported by a grant for the Intensification of the Research Tasks in the National Health Care System from Instituto de Salud Carlos III, Spain. The consumables for measurements and data analysis were supported by a Fondo de Investigación Sanitaria grant (08/0754) from the Instituto de Salud Carlos II

Efecto de los antiinflamatorios no esteroideos sobre el proceso de reclutamiento de leucocitos a focos de inflamación

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 3 de Mayo de 199