Aims:
In this pandemic, it is essential for rheumatologists and patients to know the relationship between COVID-19 and inflammatory rheumatic diseases (IRDs). We wanted to assess the role of targeted ...synthetic or biologic disease-modifying antirheumatic drugs (ts/bDMARDs) and other variables in the development of moderate-severe COVID-19 disease in IRD.
Methods:
An observational longitudinal study was conducted during the epidemic peak in Madrid (1 March to 15 April 2020). All patients attended at the rheumatology outpatient clinic of a tertiary hospital in Madrid with a medical diagnosis of IRD were included. Main outcome: hospital admission related to COVID-19. Independent variable: ts/bDMARDs. Covariates: sociodemographic, comorbidities, type of IRD diagnosis, glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Incidence rate (IR) of hospital admission related to COVID-19 was expressed per 1000 patient-months. Cox multiple regression analysis was run to examine the influence of ts/bDMARDs and other covariates on IR of hospital admission related to COVID-19.
Results:
A total of 3951 IRD patients were included (5896 patient-months). Methotrexate was the csDMARD most used. Eight hundred and two patients were on ts/bDMARDs, mainly anti-TNF agents, and Rtx. Hospital admissions related to COVID-19 occurred in 54 patients (1.36%) with an IR of 9.15 (95% confidence interval: 7–11.9). In the multivariate analysis, older, male, comorbidities, and specific systemic autoimmune conditions (Sjögren, polychondritis, Raynaud, and mixed connective tissue disease) had more risk of hospital admissions. Exposition to ts/bDMARDs did not achieve statistical significance. Use of glucocorticoids, NSAIDs, and csDMARDs dropped from the final model.
Conclusion:
This study provides additional evidence in IRD patients regarding susceptibility to moderate–severe infection related to COVID-19.
This study aimed to evaluate the role of microRNAs (miRNA) as biomarkers of treatment response in rheumatoid arthritis (RA) patients through a systematic review of the literature. The MEDLINE and ...Embase databases were searched for studies including RA-diagnosed patients treated with disease-modifying antirheumatic drugs (DMARDs) that identify miRNAs as response predictors. Review inclusion criteria were met by 10 studies. The main outcome of the study was the response to treatment, defined according to EULAR criteria. A total of 839 RA patients and 67 healthy donors were included in the selected studies. RA patients presented seropositivity for the rheumatoid factor of 74.7% and anti-citrullinated C-peptide antibodies of 63.6%. After revision, 15 miRNAs were described as treatment response biomarkers for methotrexate, anti-tumour necrosis factor (TNF), and rituximab. Among treatments, methotrexate presented the highest number of predictor miRNAs: miR-16, miR-22, miR-132, miR-146a and miR-155. The most polyvalent miRNAs were miR-146a, predicting response to methotrexate and anti-TNF, and miR-125b, which predicts response to infliximab and rituximab. Our data support the role of miRNAs as biomarkers of treatment response in RA and point to DMARDs modifying the miRNAs expression. Nevertheless, further studies are needed since a meta-analysis that allows definitive conclusions is not possible due to the lack of studies in this field.
This study aimed to identify inflammatory factors and soluble cytokines that act as biomarkers in the diagnosis and prognosis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). We ...performed a nested prospective observational case-control study of patients with RA-ILD matched by sex, age, and time since the diagnosis of RA. All participants underwent pulmonary function testing and high-resolution computed tomography. ILD was defined according to the criteria of the American Thoracic Society/European Respiratory Society; the progression of lung disease was defined as the worsening of FVC > 10% or DLCO > 15%. Inflammation-related variables included the inflammatory activity measured using the DAS28-ESR and a multiplex cytokine assay. Two Cox regression models were run to identify factors associated with ILD and the progression of ILD. The study population comprised 70 patients: 35 patients with RA-ILD (cases) and 35 RA patients without ILD (controls). A greater percentage of cases had higher DAS28-ESR (
= 0.032) and HAQ values (
= 0.003). The variables associated with RA-ILD in the Cox regression analysis were disease activity (DAS28) (HR 95% CI, 2.47 1.17-5.22;
= 0.017) and high levels of ACPA (HR 95% CI, 2.90 1.24-6.78;
= 0.014), IL-18 in pg/mL (HR 95% CI, 1.06 1.00-1.12;
= 0.044), MCP-1/CCL2 in pg/mL (HR 95% CI, 1.03 1.00-1.06;
= 0.049), and SDF-1 in pg/mL (HR 95% CI, 1.00 1.00-1.00;
= 0.010). The only variable associated with the progression of ILD was IL-18 in pg/mL (HR 95% CI, 1.25 1.07-1.46;
= 0.004). Our data support that the inflammatory activity was higher in patients with RA-ILD than RA patients without ILD. Some cytokines were associated with both diagnosis and poorer prognosis in patients with RA-ILD.
Mesenchymal stem cells (MSCs) have the ability to differentiate into different types of cells of the mesenchymal lineage, such as osteocytes, chondrocytes, and adipocytes. It is also known that under ...inflammatory stimuli or in the appropriate experimental conditions, they can also act as regulators of inflammation. Thus, in addition to their regenerating potential, their interest has been extended to their possible use in cell therapy strategies for treatment of immune disorders.
To analyze, by RNA-seq analysis, the transcriptome profiling of allogenic MSCs under RA lymphocyte activation.
We identified the differentially expressed genes in bone marrow mesenchymal stem cells after exposure to an inflammatory environment. The transcriptome profiling was evaluated by means of the precise measurement of transcripts provided by the RNA-Seq technology.
Our results evidenced the existence of blocking of both regenerative (differentiation) and immunomodulatory phenotypes under inflammatory conditions characterized by an upregulation of genes involved in immune processes and a simultaneous downregulation of genes mainly involved in regenerative or cell differentiation functions.
We conclude that the two main functions of MSCs (immunomodulation and differentiation) are blocked, at least while the inflammation is being resolved. Inflammation, at least partially mediated by gamma-interferon, drives MSCs to a cellular distress adopting a defensive state. This knowledge could be of particular interest in cases where the damage to be repaired has an important immune-mediated component.
Osteoarthritis (OA) is characterized by altered homeostasis of joint cartilage and bone, whose functional properties rely on chondrocytes and osteoblasts, belonging to mesenchymal stem cells (MSCs). ...WNT signaling acts as a hub integrating and crosstalking with other signaling pathways leading to the regulation of MSC functions. The aim of this study was to evaluate the existence of a differential signaling between Healthy and OA-MSCs during osteogenesis.
MSCs of seven OA patients and six healthy controls were isolated, characterised and expanded. During in vitro osteogenesis, cells were recovered at days 1, 10 and 21. RNA and protein content was obtained. Expression of WNT pathway genes was evaluated using RT-qPCR. Functional studies were also performed to study the MSC osteogenic commitment and functional and post-traslational status of β-catenin and several receptor tyrosine kinases.
Several genes were downregulated in OA-MSCs during osteogenesis in vitro. These included soluble Wnts, inhibitors, receptors, co-receptors, several kinases and transcription factors. Basal levels of β-catenin were higher in OA-MSCs, but calcium deposition and expression of osteogenic genes was similar between Healthy and OA-MSCs. Interestingly an increased phosphorylation of p44/42 MAPK (ERK1/2) signaling node was present in OA-MSCs.
Our results point to the existence in OA-MSCs of alterations in expression of Wnt pathway components during in vitro osteogenesis that are partially compensated by post-translational mechanisms modulating the function of other pathways. We also point the relevance of other signaling pathways in OA pathophysiology suggesting their role in the maintenance of joint homeostasis through modulation of MSC osteogenic potential.
To analyze the intestinal microbiota of patients with rheumatoid arthritis (RA) and obesity and a higher percentage of fatty tissue.
Nested case-control study of 80 RA patients and 80 age and ...sex-matched controls. Obesity was defined as a body mass index ≥ 30, and body composition using dual-energy x-ray absorptiometry. The gut microbiota was analyzed using 16 S rRNA gene sequencing; bioinformatics analysis was performed using QIIME2 and PICRUSt. Other variables included averaged 28-joint Disease Activity Score (DAS28-ESR), cytokines and adipokines. Two multivariate were constructed with obesity and fat mass index (FMI).
Obesity was more frequent in RA patients than in controls (36.3 % vs 25.1 %; p = 0.026), as was a higher FMI value (mean SE=11.6 3.9 vs 10.2 3.9; p = 0.032). Alpha and beta diversity analysis revealed differences in gut microbiota between RA patients with and without obesity. Dialister and Odoribacter were more abundant in RA patients with obesity than in RA patients without obesity, while the genus Clostridium was more abundant in RA patients without obesity. The factors associated with obesity in RA patients were age (OR 95 % CI, 1.09 1.02–1.17), mean DAS28-ESR (OR 95 % CI, 1.46 1.12–1.67), leptin levels (OR 95 % CI, 1.06 1.01–1.10), the genus Dialister (OR 95 % CI, 1.03 1.01–1.07), and the genus Clostridium (OR 95 % CI, 0.013 0.00–0.36). The associations observed for FMI were similar.
In patients with RA, obesity, and a higher percentage of fatty tissue, intestinal microbiota differed from that of controls and of the other patients. The genus Dialister was associated with obesity and FMI.
Objective: In this study, we aimed to evaluate the worldwide incidence and prevalence of ANCA-associated vasculitis (AAV). Methods: A systematic search of Medline and Embase was conducted until June ...2020 for studies that analyzed the incidence and prevalence of patients aged >16 years diagnosed with AAV in different geographical areas. A meta-analysis was undertaken to estimate the pooled incidence per million person-years and prevalence per million persons in AAV overall and for each subtype of AAV: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). The 95% confidence interval (CI) and I2 for heterogeneity were calculated. Results: The meta-analysis included 25 studies that met the inclusion criteria and covered a total of 4547 patients with AAV. Frequency increased over time. The global pooled incidence (95% CI) was 17.2 per million person-years (13.3−21.6) and the global pooled prevalence (95% CI) was 198.0 per million persons (187.0−210.0). The pooled incidence per million person-years for each AAV subtype varied from highest to lowest, as follows: GPA, 9.0; MPA, 5.9; and EGPA, 1.7. The individual pooled prevalence per million persons was, as follows: GPA, 96.8; MPA, 39.2; and EGPA, 15.6. AAV was more predominant in the northern hemisphere. By continent, a higher incidence in America and pooled prevalence of AAV was observed in America and Europe. Conclusion: The pooled incidence and prevalence of AAV seem to be increasing over time and are higher in the case of GPA. AAV was generally more frequent (incidence and prevalence) in the northern hemisphere.
Objectives:
The aim of this study was to assess the cause-specific mortality rate related to COVID-19 (CMR) in patients with rheumatic and musculoskeletal diseases (RMDs) and COVID-19 and to analyze ...the role of the different RMDs in their mortality risk.
Methods:
An observational longitudinal study was conducted during the first pandemic wave in our center. Patients with the diagnosis of RMDs and COVID-19 were included. Main outcome is the death related to COVID-19. Independent variable – type of RMDs: autoimmune rheumatic diseases (ARD), such as chronic inflammatory arthritis (CIA) and connective tissue diseases (CTD) and non-autoimmune Rheumatic Diseases (non-ARD). Survival techniques were used to estimate the CMR per 1000 patients-month with a 95% confidence interval (CI), and Cox multivariate regression analysis was run to examine the effect of ARD compared to non-ARD on mortality risk adjusted by confounders. Results were expressed by Hazard Ratio (HR) and CI.
Results:
Overall, 405 patients were included (642.5 patients-month). During the study period, 44 (10.86%) deaths were recorded. CMR was 68.48 (50.96–92.01). After adjusting for confounders, HR of mortality in ARD compared to non-ARD did not achieve statistical significance HR: 1.15 (0.64–2.07), neither CTD versus CIA nor CTD versus non-ARD. Age and certain comorbidities which are being diagnosed in March compared to April or May HR: 2.43 (1.1–5.55) increased the mortality risk. Glucocorticoids and disease-modifying antirheumatic drugs (DMARDs) dropped from the final model.
Conclusion:
In patients with RMDs and COVID-19, CMR was 6.8% patients-month. This study shows that mortality risk is higher in males, older patients, and similar between CTD, CIA, and non-ARD. COVID-19 management improved after the first month of pandemic.
Plain Language Summaries
Mortality related to the outbreak of COVID-19 in patients with rheumatic and musculoskeletal diseases
Why was this study done?
- To report the COVID-19-specific mortality rate in patients with a variety of RMDs during the first pandemic peak in a tertiary hospital in Madrid and to analyze the role of specific types of ARD and other possible factors in the risk of death related to COVID-19.
What did the researchers do?
- We performed a retrospective observational study during the first wave of the COVID-19 pandemic in Madrid, Spain.
What did the researchers find?
- In this study, neither the different diagnoses of RMDs, including CIA, CTD, or non-ARD disease or its treatment were not implicated as a potential risk of death related to COVID-19
- In consonance with other studies, RMDs patients and COVID-19, older age, male sex, and certain comorbidities implied more mortality risk
- Our data reflect COVID-19 severity in a particular context, time, and population. In times of the absence of COVID-19 vaccine, healthcare, social, and political measures taken to contain the coronavirus outbreak have worked properly.
What do the findings mean?
- The presence of comorbidities in RMDs patients represents a greater risk than the different types of RMDs themselves, in the development of COVID-19 fatal outcome. It is important to integrate the control of comorbidities in the daily management.
In this study of the alterations of Glypicans 1 to 6 (GPCs) and Notum in plasma, bone marrow mesenchymal stromal cells (BM-MSCs) and osteoblasts in Osteoarthritis (OA), the levels of GPCs and Notum ...in the plasma of 25 patients and 24 healthy subjects were measured. In addition, BM-MSCs from eight OA patients and eight healthy donors were cultured over a period of 21 days using both a culture medium and an osteogenic medium. Protein and gene expression levels of GPCs and Notum were determined using ELISA and qPCR at 0, 7, 14 and 21 days. GPC5 and Notum levels decreased in the plasma of OA patients, while the BM-MSCs of OA patients showed downexpression of GPC6 and upregulation of Notum. A decrease in GPC5 and Notum proteins and an increase in GPC3 were found. During osteogenic differentiation, elevated GPCs 2, 4, 5, 6 and Notum mRNA levels and decreased GPC3 were observed in patients with OA. Furthermore, the protein levels of GPC2, GPC5 and Notum decreased, while the levels of GPC3 increased. Glypicans and Notum were altered in BM-MSCs and during osteogenic differentiation from patients with OA. The alterations found point to GPC5 and Notum as new candidate biomarkers of OA pathology.
Objectives
To describe the characteristics of patients between late-onset rheumatoid arthritis (LORA) with young-onset (YORA), and analyze their association with cumulative inflammatory burden.
...Methods
We performed a nested cohort study in a prospective cohort comprising 110 patients with rheumatoid arthritis (RA) and 110 age- and sex-matched controls. The main variable was cumulative inflammatory activity according to the 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR). High activity was defined as DAS28 ≥ 3.2 and low activity as DAS28 < 3.2. The other variables recorded were inflammatory cytokines, physical function, and comorbid conditions. Two multivariate models were run to identify factors associated with cumulative inflammatory activity.
Results
A total of 22/110 patients (20%) met the criteria for LORA (≥ 60 years). Patients with LORA more frequently had comorbid conditions than patients with YORA and controls. Compared with YORA patients, more LORA patients had cumulative high inflammatory activity from onset 13 (59%) vs. 28 (31%);
p
= 0.018 and high values for CRP (
p
= 0.039) and IL-6 (
p
= 0.045). Cumulative high inflammatory activity in patients with RA was associated with LORA OR (95% CI) 4.69 (1.49–10.71);
p
= 0.008, smoking OR (95% CI) 2.07 (1.13–3.78);
p
= 0.017, anti–citrullinated peptide antibody OR (95% CI) 3.24 (1.15–9.13);
p
= 0.025, average Health Assessment Questionnaire (HAQ) score OR (95% CI) 2.09 (1.03–14.23);
p
= 0.034, and physical activity OR (95% CI) 0.99 (0.99–0.99);
p
= 0.010. The second model revealed similar associations with inflammatory activity in patients with LORA.
Conclusion
Control of inflammation after diagnosis is poorer and comorbidity more frequent in patients with LORA than in YORA patients and healthy controls.
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