The latest medical research on Rheumatology

The research magnet gathers the latest research from around the web, based on your specialty area. Below you will find a sample of some of the most recent articles from reputable medical journals about rheumatology gathered by our medical AI research bot.

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Altered properties of endothelial cells and mesenchymal stem cells underlying the development of scleroderma-like vasculopathy in Klf5+/- ;Fli1+/- mice.

Arthritis Rheumatol

We previously established a new animal model (Klf5+/- ;Fli1+/- mice) broadly recapitulating fundamental pathologic features of systemic sclerosis (SSc). SSc vasculopathy is believed to occur as a result of impaired vascular remodeling, but its detailed mechanism has remained unknown. To address this issue, we investigated the properties of dermal microvascular endothelial cells (DMECs), bone marrow-derived endothelial progenitor cells (BM-EPCs) and bone marrow-derived mesenchymal stem cells (BM-MSCs), a precursor of pericytes, in Klf5+/- ;Fli1+/- mice.

Neovascularization and angiogenesis were assessed by in vivo Matrigel plug assay and in vitro tube formation assay, respectively. The properties of BM-EPCs and BM-MSCs were assessed in in vitro studies. Dermal vasculature was visualized in vivo by FITC-dextran injection.

Neovascularization was diminished in skin-embedded Matrigel plug in Klf5+/- ;Fli1+/- mice. Klf5+/- ;Fli1+/- DMECs showed defective tubulogenic activity, decreased expression of VE-cadherin and CD31, and imbalance of Notch1/delta-like ligand 4, suggesting that angiogenesis and anastomosis are disturbed. Klf5+/- ;Fli1+/- BM-MSCs exhibited enhanced proliferation, migration and collagen production by transforming growth factor-β1, indicating the preferential differentiation into myofibroblasts rather than pericytes. Klf5+/- ;Fli1+/- BM-EPCs displayed the transition toward mesenchymal cells, suggesting that vasculogenesis is impaired. Wound healing was delayed in Klf5+/- ;Fli1+/- mice (15.67 ± 0.82 days versus 13.50 ± 0.84 days; P = 0.0017), and vascular network was poorly developed in wound scar tissue.

Klf5+/- ;Fli1+/- mice represent impaired neovascularization and vascular maturation similar to those of SSc at least partially due to the induction of SSc-like properties in DMECs, BM-EPCs and BM-MSCs, indicating the critical contribution of KLF5 and Fli1 deficiency in vascular cells and related precursors to SSc vasculopathy.

Effects of vitamin D supplementation on disabling foot pain in patients with symptomatic knee osteoarthritis.

Arthritis Care Res

This study aims to determine whether vitamin D supplementation or maintaining sufficient vitamin D level reduces foot pain over two years in patients with symptomatic knee OA.

A post hoc study was conducted from a randomized double-blind placebo-controlled trial named the VItamin D Effect on Osteoarthritis (VIDEO) study. Symptomatic knee OA patients with serum 25-hydroxyvitamin D levels between 12.5 nmol/L to 60 nmol/L were included and randomly allocated to either monthly vitamin D3 or placebo treatment (1:1) for 2 years. Manchester Foot Pain and Disability Index (MFPDI) was used to evaluate foot pain and Disabling foot pain was defined as at least one of the 10 functional limitation items (items 1-9,11) being documented as on 'most/every day(s)' in the last month. A repeated-measure mixed effect model was used to analyze the change of MFPDI scores between groups adjusting for potential confounders.

A total of 413 patients with a mean age of 63.2 years (49.7% males) were enrolled and 340 completed the study. The mean MFPDI score was 22.8±7.3, with 23.7% participants having disabling foot pain at baseline. There were significant differences in MFPDI scores change between groups over 2 years, with more improvements in vitamin D group than in placebo group (-0.03 vs. 1.30, P=0.013) and more improvement in those maintaining sufficient vitamin D levels (n=226) than those who did not (n=114) (-0.09 vs. 2.19, P=0.001).

Vitamin D supplementation and maintenance of sufficient vitamin D levels may improve foot pain in those with knee OA.

Autoantibodies to Malondialdehyde-Acetaldehyde Are Detected Prior to Rheumatoid Arthritis Diagnosis and After Other Disease Specific Autoantibodies.

Arthritis Rheumatol

To examine serum autoantibodies to malondialdehyde-acetaldehyde (MAA) prior to rheumatoid arthritis (RA) diagnosis.

Anti-MAA antibody isotypes, anti-CCP2, and RF-IgM were measured in pre- and post-RA diagnosis samples (n=214 cases, 210 controls). The timing of elevations in autoantibody concentrations relative to RA diagnosis was explored using separate mixed-models for each antibody and/or isotype. Associations between pre-diagnosis autoantibody concentrations in cases were examined using mixed effects linear regression models.

IgG (log2 difference 0.34) and IgA (log2 difference 0.43) anti-MAA antibody concentrations in cases diverged from controls 3.0 and 2.3 years, respectively, pre-RA diagnosis (p <0.05). There was no evidence of case-control divergence for IgM anti-MAA antibody. Anti-CCP2 and RF-IgM concentrations diverged between cases and controls beginning 17.6 and 7.2 years, respectively, prior to RA diagnosis. All three anti-MAA antibody isotypes were significantly associated with anti-CCP2 antibody and RF concentrations pre-diagnosis (β = 0.22-0.27 for RF-IgM; β = 0.44-0.93 for anti-CCP2; p <0.001).

IgG and IgA anti-MAA autoantibodies are elevated pre-RA diagnosis but appear later in the pre-clinical course than anti-CCP2 or RF. These results suggest that MAA formation and anti-MAA immune responses could have a role in the transition from subclinical autoimmunity to clinically apparent arthritis.

Physiological target, molecular evolution and pathogenic functions of a monoclonal ACPA obtained from an RA patient.

Arthritis Rheumatol

We previously isolated a human monoclonal anti-citrullinated protein/peptide antibody (ACPA), CCP-Ab1, which recognizes various citrullinated antigens, from a patient with rheumatoid arthritis (RA). In this study, we aimed to explore the physiological target for CCP-Ab1 and the role of molecular evolution, through affinity maturation of CCP-Ab1, in the onset and the exacerbation of RA.

We identified and purified the target protein of CCP-Ab1 in plasma, under native conditions. Then, we generated germline-reverted CCP-Ab1 (GL-rev CCP-Ab1) and compared its reactivity to mature CCP-Ab1. Finally, we analyzed the function of CCP-Ab1 and GL-rev CCP-Ab1 in the onset or the exacerbation of autoimmune arthritis using autoimmune arthritis-prone SKG mice.

CCP-Ab1 bound citrullinated fibrinogen under native conditions. GL-rev CCP-Ab1 drastically reduced the binding affinity to citrullinated fibrinogen (p < 0.05). Also, the elements implicated in GL-rev CCP-Ab1 binding to citrullinated-peptide, cfc1-cyc were almost identical to those bound by CCP-Ab1. CCP-Ab1, but not GL-rev CCP-Ab1, induced significant exacerbation of experimental arthritis when administered into SKG mice (p < 0.05). IL-6 production, in both joint tissue and serum, was observed in the CCP-Ab1-treated SKG mice but not in the GL-rev CCP-Ab1-treated group (p < 0.05). Furthermore, the immune complex formed by CCP-Ab1 and fibrinogen was detected in the synovial tissues in CCP-Ab1-administered mice (p < 0.05).

Our data show that germline-encoded CCP-Ab1, which binds weakly to citrullinated fibrinogen, undergoes hypermutation through activation of naïve B cells by citrullinated peptides/proteins, stimulating high reactivity to citrullinated fibrinogen. These findings deepen our understanding of the role of molecular evolution of ACPAs in the onset/exacerbation of RA.

Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: an open-label cohort study.

Annals of the Rheumatic Diseases

To assess the safety and efficacy of interleukin (IL)-6 blockade with sarilumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation.

We conducted an open-label study of sarilumab in severe COVID-19 pneumonia (PaO2/FiO2 <300 mm Hg) with hyperinflammation (elevated inflammatory markers and serum IL-6 levels). Sarilumab 400 mg was administered intravenously in addition to standard of care and results were compared with contemporary matched patients treated with standard of care alone. Clinical improvement, mortality, safety and predictors of response were assessed at 28 days.

Twenty-eight patients were treated with sarilumab and 28 contemporary patients receiving standard of care alone were used as controls. At day 28 of follow-up, 61% of patients treated with sarilumab experienced clinical improvement and 7% died. These findings were not significantly different from the comparison group (clinical improvement 64%, mortality 18%; p=NS). Baseline PaO2/FiO2 ratio >100 mm Hg and lung consolidation <17% at CT scan predicted clinical improvement in patients treated with sarilumab. Median time to clinical improvement in patients with lung consolidation <17% was shorter after sarilumab (10 days) than after standard treatment (24 days; p=0.01). The rate of infection and pulmonary thrombosis was similar between the two groups.

At day 28, overall clinical improvement and mortality in patients with severe COVID-19 were not significantly different between sarilumab and standard of care. Sarilumab was associated with faster recovery in a subset of patients showing minor lung consolidation at baseline.

Associations between Smoking and Systemic Lupus Erythematosus (SLE)-Related Cytokines and Chemokines among US Female Nurses.

Arthritis Care Res

Smoking has been associated with increased systemic lupus erythematosus (SLE) risk, but the biologic basis for this association is unknown. We investigated whether women's smoking was positively associated with SLE-associated pro-inflammatory chemokines/cytokines, [stem cell factor (SCF), B-lymphocyte stimulator (BLyS), interferon-inducible protein-10 (IP-10), interferon-alpha (IFN-α)]; or negatively associated with anti-inflammatory cytokine interleukin-10 (IL-10)]; and whether associations were modified by SLE-related autoantibody status.

The Nurses' Health Study (NHS, n=121,700) and NHSII (n=116,429) cohorts were begun in 1976 and 1989. In 1988-1990 (NHS) and 1996-1999 (NHSII), ~25% participants donated blood samples. We identified 1177 women without SLE with banked samples and tested by ELISA for chemokines/cytokines as well as anti-Sm, -Ro/SSA, La/SSB and RNP. Antinuclear antibodies (ANA) were detected by HEp-2 cell indirect immunofluorescence and anti-double-stranded DNA antibodies and were assayed by ELISA. Smoking was assessed until blood draw. Separate tobit and linear regression analyses, adjusted for potential confounders, modeled associations between smoking and log-transformed chemokine/cytokine concentrations. Analyses were stratified by autoantibody status. Effect estimates were calculated as ratios of geometric means, expressed as % differences.

Among the 15% current/recent vs. 85% past/never smokers, BLyS levels were 8.7% higher (p<0.01), and were 24% higher (p<0.0001) among those ANA+. Current/recent smokers had IL-10 concentrations 46% lower (p<0.01) than past/never smokers; each 10 pack-years of smoking was associated with -17% IL-10 (p <0.001). Smoking was not associated with IP-10 or SCF.

Elevated BLyS and lower IL-10 levels among current smokers, particularly among ANA+ women, may be involved in SLE pathogenesis.

A Systematic Literature Review of Residual Symptoms and Unmet Need in Patients with Rheumatoid Arthritis.

Arthritis Care Res

To evaluate the nature and burden of residual disease in rheumatoid arthritis (RA) in patients who meet treatment targets. Secondly, for those who did not meet targets, evaluate how much is due to patient symptoms.

Prospective and retrospective studies were searched in MEDLINE, Embase, and Cochrane Library in the English language from January 1, 2008, to April 18, 2018; conference abstracts (from January 2016 to April 2018) and reference lists of relevant studies were also screened.

Of 8,339 records identified, 55 were included in the review; 53 were unique studies, including 10 randomized controlled trials. Of these, 48 reported on patients who achieved low disease activity (LDA) or remission. Studies varied in population, treatment goals, and outcome reporting. The proportions of patients with residual symptoms in these studies varied by the definitions used for LDA or remission and were more often reported in patients with LDA than those in remission. The most commonly reported outcome measures were functional disability (n=34 studies), tender or swollen joints (n=18), pain (n=17), patient global assessment (n=15), and fatigue (n=14). However, few studies reported the percentage of patients achieving a specific threshold, which could then be used to easily define the presence of residual symptoms.

Residual symptoms are present in some patients despite their achieving LDA or remission, highlighting an unmet need, especially with respect to improving pain, fatigue, and function. Standardized reporting in future observational studies would facilitate better understanding of this issue in defined RA populations.

Biomarker development for axial spondyloarthritis.

Nature Reviews Rheumatology

The term axial spondyloarthritis (axSpA) encompasses a heterogeneous group of diseases that have variable presentations, extra-articular manifestat...

Taurine metabolism aggravates the progression of lupus by promoting the function of plasmacytoid dendritic cells.

Arthritis Rheumatol

Type I interferons (IFN-I) are critical for the development of systemic lupus erythematosus (SLE). Metabolic abnormalities cause dysregulation of multiple immune cells, but the metabolic regulation of IFN-I production is far from clarified in SLE. This study was conducted to define amino acid metabolism features in SLE, and explore the function of disease-relevant metabolite on the control of plasmacytoid dendritic cells (pDCs) mediated IFN-I production and the progression of SLE.

Metabolomic profiling of the serum from SLE patients and healthy controls was performed by mass spectrometry (MS). The effects of SLE-related metabolites on IFN-I production were explored on human and mouse pDCs. The ROS levels of pDCs from wild type and NCF1-/- mice were measured by flow cytometry. Mechanisms were investigated by RNA sequencing and immunoblots. In vivo effects of SLE-relevant metabolite were systemically analyzed on B6.Cg-Sle1NZM2410/Aeg Yaa/DcrJ mice.

Taurine was higher in SLE patients' serum compared with healthy controls (P < 0.001) and RA patients (P < 0.001). Taurine content was positively correlated with disease activity and the expression of IFN signature genes. The addition of taurine facilitated IRF7 phosphorylation and enhanced IFN-I production by reducing the ROS levels in pDC in an NCF1-dependent manner. Supplement of taurine promoted IFN-I induced genes' expression, activated lymphocyte, increased autoantibodies, and proteinuria, leading to more serious nephritis.

Taurine metabolism is involved in the development of SLE through enhancing pDC mediated IFN-I production. Targeted inhibition of taurine or taurine restricted diet has therapeutic potential in SLE.

Population characteristics as important contextual factors in rheumatological trials: an exploratory meta-epidemiological study from an OMERACT Working Group.

Annals of the Rheumatic Diseases

To explore whether trial population characteristics modify treatment responses across various interventions, comparators and rheumatic conditions.

In this meta-epidemiological study, we included trials from systematic reviews available from the Cochrane Musculoskeletal Group published up to 23 April 2019 in Cochrane Library with meta-analyses of five or more randomised controlled trials (RCTs) published from year 2000. From trial reports, we extracted data on 20 population characteristics. For characteristics with sufficient data (ie, available for ≥2/3 of the trials), we performed multilevel meta-epidemiological analyses.

We identified 19 eligible systematic reviews contributing 187 RCTs (212 comparisons). Only age and sex were explicitly reported in ≥2/3 of the trials. Using information about the country of the trials led to sufficient data for five further characteristics, that is, 7 out of 20 (35%) protocolised characteristics were analysed. The meta-regressions showed effect modification by economic status, place of residence, and, nearly, from healthcare system (explaining 4.8%, 0.9% and 1.5% of the between-trial variation, respectively). No effect modification was demonstrated from age, sex, patient education/health literacy or predominant religion.

This study demonstrates the scarce reporting of most population characteristics, hampering investigation of their impact with meta-research. Our sparse results suggest that place of residence (ie, continent of the trial), economic status (based on World Bank classifications) and healthcare system (based on WHO index for health system performance) may be important in explaining the variation in treatment response across trials. There is an urgent need for consistent reporting of important population characteristics in trials.

CRD42019127642.

Quantitative analysis of pulmonary vasculature in systemic sclerosis at spirometry-gated chest CT.

Annals of the Rheumatic Diseases

To prospectively investigate whether differences in pulmonary vasculature exist in systemic sclerosis (SSc) and how they are distributed in patients with different pulmonary function.

Seventy-four patients with SSc undergoing chest CT scan for interstitial lung disease (ILD) screening or follow-up were prospectively enrolled. A thorough clinical, laboratory and functional evaluation was performed the same day. Chest CT was spirometry gated at total lung capacity and images were analysed by two automated software programs to quantify emphysema, ILD patterns (ground-glass, reticular, honeycombing), and pulmonary vascular volume (PVV). Patients were divided in restricted (FVC% <80, DLco%<80), isolated DLco% reduction (iDLco- FVC%≥80, DLco%<80) and normals (FVC%≥80, DLco%≥80). Spearman ρ, Mann-Whitney tests and logistic regressions were used to assess for correlations, differences among groups and relationships between continuous variables.

Absolute and lung volume normalised PVV (PVV/LV) correlated inversely with functional parameters and positively with all ILD patterns (ρ=0.75 with ground glass, ρ=0.68 with reticular). PVV/LV was the only predictor of DLco at multivariate analysis (p=0.007). Meanwhile, the reticular pattern prevailed in peripheral regions and lower lung thirds, PVV/LV prevailed in central regions and middle lung thirds. iDLco group had a significantly higher PVV/LV (2.2%) than normal (1.6%), but lower than restricted ones (3.8%).

Chest CT in SSc detects a progressive increase in PVV/LV as DLco decreases. Redistribution of perfusion to less affected lung regions rather than angiogenesis nearby fibrotic lung may explain the results. Further studies to ascertain whether the increase in PVV/LV reflects a real increase in blood volume are needed.

Use of physiotherapy in patients with osteoarthritis in Germany- an analysis of a linkage of claims and survey data (from the PROCLAIR project).

Arthritis Care Res

To examine utilization of physiotherapy (PT) and predictors for its use in individuals with osteoarthritis (OA) focusing on sociodemographic and disease-related factors.

For this cross-sectional study 657,807 persons (30-79 years) diagnosed with hip, knee or polyarticular OA were identified in claims data. In 2016 a questionnaire including information on disease status, demography and socioeconomics was sent to a random sample of 8,995 patients, stratified by sex, age and type of diagnosis. Claims data of 2016 included utilization and type of PT as well as the prescribing medical specialist and were linked to questionnaire data. Multivariable logistic regression was conducted to determine variables associated with the use of PT.

3,564 (40%) persons completed the questionnaire and agreed linking questionnaire and claims data (69% female, mean age: 66.5 years). In 2016 50% of the study population received at least once PT, and women more frequently than men (53% vs. 43%). Most PT was prescribed by orthopedists (45%) and general practitioners (32%). Multivariable logistic regression showed that women, higher household income, having both, hip and knee OA, lower functional status, higher disease activity, and persons living in the eastern, southern and western states of Germany were associated with an increased utilization of PT.

Considering current guideline recommendations and that even one-third of OA patients with high functional impairment and/or pain did not receive PT in the last 12 months, there is a large potential for improvement. This is also true for men and persons with low income.