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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Pro-inflammatory histidyl-tRNA synthetase-specific CD4+ T cells in the blood and lung of patients with idiopathic inflammatory myopathies.

Arthritis Rheumatol

Autoantibodies targeting histidyl-tRNA synthetase (HisRS, or anti-Jo1) are common in idiopathic inflammatory myopathies (IIM) and anti-synthetase syndrome (ASS). We aimed to investigate immunity against HisRS in blood and lungs of patients with IIM/ASS.

Bronchoalveolar lavage fluid (BALF), BALF cells and peripheral blood mononuclear cells (PBMCs) from IIM/ASS (n=24) patients were stimulated with full-length HisRS-protein or a HisRS-derived peptide (HisRS11-23 ). BALF and PBMCs from sarcoidosis patients (n=7) and healthy controls (HCs, n=12) were included as controls. CD4+ T-cell response was assessed by CD40L upregulation and cytokine expression using flow cytometry. Anti-Jo1 autoantibody response in serum and BALF was assessed by ELISA. Lung biopsies (n=14) were investigated by immunohistochemistry.

In BALF, CD4+ T cells from 3/4 IIM/ASS responded to HisRS-protein stimulation (median CD40L fold-change: 3.6; 2.7-14.7) and 2/3 IIM/ASS had the highest responses to HisRS11-23 (median CD40L fold-change: 88; 27-149). In PBMCs, CD4+ T cells from 14/18 IIM/ASS responded to HisRS-protein (median fold-change: 7.38; IQR, 2.69-31.86, p<0.001) whereas HisRS11-23 response was present in 11/14 IIM/ASS (median fold-change: 3.4, IQR 1.87-10.9, p<0.001). In the control group, there was a HisRS11-23 response in 3/7 sarcoidosis (median CD40L fold-change: 2.09; IQR, 1.45-3.29), and in 5/12 HCs (median fold-change: 2; IQR, 1.89-2.42). CD4+ T cells from IIM/ASS displayed a pronounced Th1 phenotype in BALF when compared to PBMCs (p<0.001), producing high amounts of IFNγ and IL-2 following stimulation. Anti-Jo1 autoantibodies were detected in BALF as well as germinal center (GC)-like structures in lung biopsies of IIM/ASS.

We report the pronounced presence of HisRS-reactive CD4+ T cells in PBMCs and BALF cells of IIM/ASS patients compared to sarcoidosis patients and HCs. This combined with the presence of anti-Jo1 autoantibodies in BALF, and GC-like structures in the lungs suggest that immune activation against HisRS might take place within the lungs of IIM/ASS patients. This article is protected by copyright. All rights reserved.

Neutrophil Extracellular Traps in Tissue and Periphery in Juvenile Dermatomyositis.

Arthritis Rheumatol

Neutrophils are key immune cells participating in host defense through several mechanisms, including the formation of neutrophil extracellular traps (NETs). The role of neutrophils in juvenile dermatomyositis (JDM) is not known.

Electron microscopy was used to identify neutrophils in tissue. NETs were also imaged using fluorescence microscopy, and quantified by an MPO-DNA ELISA in plasma from healthy children (n=20), disease controls (n=29), JDM patients (n=66), and JDM patients with history of calcifications (n=20). Clinical data included disease activity scores and complement C4 levels. Levels of immune complexes (ICs) and calprotectin were analyzed by ELISA.

Using electron microscopy, neutrophils were found to infiltrate affected muscle tissue, engulfing deposited calcium crystals. Uptake of the crystals led to neutrophil activation (p<0.01) and subsequent PI3K- and NADPH oxidase-dependent, but PAD4-independent NET formation, which contained mitochondrial DNA (p<0.05) as confirmed in vivo and in vitro (p<0.001, and p<0.01). Peripheral NET levels were associated with calcinosis (p=0.01), ICs (p=0.008), and IL-8 levels (p=0.004). JDM children had an impaired NET clearance (p=0.01), associated with autoantibody profiles, including MDA-5 (p=0.005), and depressed complement C4 levels (r=-0.72, p=0.002). Further, JDM children had evidence of neutrophil activation, with elevated levels of peroxidase activity (p=0.02) and calprotectin (p<0.01), associated with disease activity (p=0.007), and dyslipidemia (OR 4.7, p<0.05).

Our investigation reports novel mechanisms of both calcium crystal-mediated neutrophil activation and cell death in JDM pathophysiology. Targeting this pathway may reduce the frequency and extent of calcinosis, as well as prevent long-term development of co-morbidities, including atherosclerosis.

Genetic and non-genetic mimics should be considered before applying interstitial pneumonia with autoimmune features (IPAF) criteria.

Arthritis Rheumatol

We appreciate the letter written by Drs. Silva-Carmona and Vogel highlighting COPA syndrome and agree with the importance of considering a genetic ...

Cardiovascular risk assessment in patients with ANCA-associated vasculitis.

Arthritis Rheumatol

In a post hoc analysis of the Rituximab for ANCA-associated Vasculitis (RAVE) trial, Wallace et al. evaluated changes in serum lipid levels followi...

Genetic Disorders should be Considered before Diagnosing Interstitial Pneumonia with Autoimmune Features (IPAF): Comment on the Article by Wilfong et al.

Arthritis Rheumatol

We read with great interest the recent review by Wilfong and colleagues on Interstitial Pneumonia with Autoimmune Features (IPAF) (1). We agree tha...

Reply to: Cardiovascular risk assessment in patients with ANCA-associated vasculitis.

Arthritis Rheumatol

We thank Moiseev et al for their comments regarding lipid levels in AAV. We would like to further discuss the assessment of cardiovascular risk in ...

2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus.

Annals of the Rheumatic Diseases

To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).

This international initiative had four phases. (1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort and a patient survey. (2) Criteria reduction by Delphi and nominal group technique exercises. (3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. (4) Refinement of weights and threshold scores in a new derivation cohort of 1001 subjects and validation compared with previous criteria in a new validation cohort of 1270 subjects.

The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in seven clinical (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunological (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria.

These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered and weighted criteria reflect current thinking about SLE and provide an improved foundation for SLE research.

Vasodilators and low-dose acetylsalicylic acid are associated with a lower incidence of distinct primary myocardial disease manifestations in systemic sclerosis: results of the DeSScipher inception cohort study.

Annals of the Rheumatic Diseases

To investigate the influence of vasodilator drugs on the occurrence of features depending on myocardial ischaemia/fibrosis (ventricular arrhythmias, Q waves, cardiac blocks, pacemaker implantation, left ventricular ejection fraction (LVEF) <55%, and/or congestive heart failure and sudden cardiac death) in systemic sclerosis (SSc).

601 patients with SSc were enrolled from 1 December 2012 to 30 November 2015 and had a second visit 0.5-4 years apart. 153 received no vasodilators; 448 received vasodilator therapy (ie, calcium channel blockers and/or ACE inhibitors or angiotensin II receptor blockers or combinations of them), 89 of them being also treated with either endothelin receptor antagonists or PDE5 inhibitors or prostanoids. Associations between the occurrence of myocardial disease manifestations and any demographic, disease and therapeutic aspect were investigated by Cox regression analysis. A Cox frailty survival model with centre of enrolment as random effect was performed.

During 914 follow-up patient-years, 12 ventricular arrhythmias, 5 Q waves, 40 cardiac blocks, 6 pacemaker implantations and 19 reduced LVEF and/or congestive heart failure (CHF) occurred. In multivariate Cox regression analysis, vasodilator therapy was associated with a lower incidence of ventricular arrhythmias (p=0.03); low-dose acetylsalicylic acid (ASA) with a lower incidence of cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.02); active disease with a higher incidence of LVEF <55% and/or CHF and cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.05).

The present study might suggest a preventative effect on the occurrence of distinct myocardial manifestations by vasodilator therapy and low-dose ASA.

Myeloablation followed by autologous stem cell transplantation normalises systemic sclerosis molecular signatures.

Annals of the Rheumatic Diseases

In the randomised scleroderma: Cyclophosphamide Or Transplantation (SCOT trial) (NCT00114530), myeloablation, followed by haematopoietic stem cell transplantation (HSCT), led to improved clinical outcomes compared with monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc). Herein, the study aimed to determine global molecular changes at the whole blood transcript and serum protein levels ensuing from HSCT in comparison to intravenous monthly CYC in 62 participants enrolled in the SCOT study.

Global transcript studies were performed at pretreatment baseline, 8 months and 26 months postrandomisation using Illumina HT-12 arrays. Levels of 102 proteins were measured in the concomitantly collected serum samples.

At the baseline visit, interferon (IFN) and neutrophil transcript modules were upregulated and the cytotoxic/NK module was downregulated in SSc compared with unaffected controls. A paired comparison of the 26 months to the baseline samples revealed a significant decrease of the IFN and neutrophil modules and an increase in the cytotoxic/NK module in the HSCT arm while there was no significant change in the CYC control arm. Also, a composite score of correlating serum proteins with IFN and neutrophil transcript modules, as well as a multilevel analysis showed significant changes in SSc molecular signatures after HSCT while similar changes were not observed in the CYC arm. Lastly, a decline in the IFN and neutrophil modules was associated with an improvement in pulmonary forced vital capacity and an increase in the cytotoxic/NK module correlated with improvement in skin score.

HSCT contrary to conventional treatment leads to a significant 'correction' in disease-related molecular signatures.

2019 EULAR recommendations for the generic core competences of health professionals in rheumatology.

Annals of the Rheumatic Diseases

To maintain and optimise the quality of care provided by health professionals in rheumatology (HPRs), adequate educational offerings are needed. This task force (TF) aimed to develop evidence-based recommendations for the generic core competences of HPRs, with specific reference to nurses, physical therapists (PTs) and occupational therapists (OTs) to serve as a basis for their postgraduate education.

The EULAR standardised operating procedures for the development of recommendations were followed. A TF including rheumatologists, nurses, PTs, OTs, patient-representatives, an educationalist, methodologists and researchers from 12 countries met twice. In the first TF meeting, 13 research questions were defined to support a systematic literature review (SLR). In the second meeting, the SLR evidence was discussed and recommendations formulated. Subsequently, level of evidence and strength of recommendation were assigned and level of agreement (LoA) determined (0-10 rating scale).

Three overarching principles were identified and 10 recommendations were developed for the generic core competences of HPRs. The SLR included 79 full-text papers, 20 of which addressed the competences, knowledge, skills, attitudes and/or educational needs of HPRs from multiple professions. The average LoA for each recommendation ranged from 9.42 to 9.79. Consensus was reached both on a research and educational agenda.

Evidence and expert opinion informed a set of recommendations providing guidance on the generic core competences of HPRs. Implementation of these recommendations in the postgraduate education of HPRs at the international and national level is advised, considering variation in healthcare systems and professional roles.

Genetic deficiency of IFNγ reveals IFNγ-independent manifestations of murine Hemophagocytic Lymphohistiocytosis.

Arthritis Rheumatol

Familial hemophagocytic lymphohistiocytosis (FHL) is a complex cytokine storm syndrome caused by genetic abnormalities rendering CD8+ T cells and NK cells incapable of cytolytic killing. Murine models of FHL have identified interferon-gamma (IFNγ) made by CD8+ T cells as a critical mediator of disease, with an IFNγ-blocking antibody (Emapalumab) recently receiving FDA approval. However, development of hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) in patients who are genetically unresponsive to IFNγ questions the absolute necessity of IFNγ in driving disease. The purpose of this study was to determine the necessity for IFNγ in driving HLH.

IFNγ-/- Prf1-/- mice were infected with LCMV and HLH immunopathologic features, including survival, weight-loss, cytopenias, cytokine profiles, and immune cell phenotypes were assessed. Mixed bone marrow chimeras were created to determine the immune-cell intrinsic role of IFNγR-signaling. CD8+ T cell depletion and IL-33:ST2 blockade was performed using monoclonal antibodies.

LCMV infection of IFNγ-/- Prf1-/- mice results in severe HLH-like disease. CD8+ T cells, and the IL-33:ST2 axis remain essential mediators of disease, however, IFNγ-independent HLH immunopathology correlates with 10-15 fold increased neutrophilia (p<0.001) and an altered cytokine milieu dominated by IL-6, IL-1β, and GM-CSF (p<0.05). Furthermore, IFNγ regulates CD8+ T cell expression of GM-CSF, and neutrophil survival.

IFNγ is not necessary for development of fulminant HLH requiring physicians to consider case-by-case treatment strategies. Use of therapies that target upstream activators of CD8+ T cells, such as IL-33:ST2 signaling, may be more universally applicable treatment options that ameliorate both IFNγ-dependent and -independent manifestations of HLH/MAS. This article is protected by copyright. All rights reserved.

Disordered Antigens and Epitope Overlap Between Anti-Citrullinated Protein Antibodies and Rheumatoid Factor in Rheumatoid Arthritis.

Arthritis Rheumatol

Anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF) are commonly present in rheumatoid arthritis without clear rationale for their coexistence. Moreover, autoantibodies develop against proteins with different post-translational modifications and native proteins without obvious unifying characteristics of the antigens. Our objective was to broadly evaluate autoantibody binding in seronegative and seropositive rheumatoid arthritis to identify novel features of reactivity.

An array was created with 172,828 native, citrulline-containing, and homocitrulline-containing peptides derived primarily from proteins citrullinated in the rheumatoid joint. IgG and IgM binding to peptides were compared for CCP+RF+, CCP+RF-, CCP-RF+, and CCP-RF- rheumatoid arthritis versus controls (n=12). IgG-bound and endogenously citrullinated peptides were analyzed for amino acid patterns and predictors of intrinsic disorder, i.e. unstable three-dimensional structure. Binding to IgG-derived peptides was specifically evaluated. ELISA confirmed key results.

Broadly, CCP+RF+ subjects had high and CCP+RF- and CCP-RF+ subjects had modest citrulline-specific IgG binding to array peptides (median z-scores: 3.02, 1.42, 0.75, respectively, p<0.0001). All rheumatoid arthritis groups had low homocitrulline-specific binding. CCP+RF+ subjects had moderate IgG binding to native peptides (median z-score 2.38, p<0.0001). The highest IgG binding was to citrulline-containing peptides, irrespective of protein identity, especially if citrulline was adjacent to glycine or serine, motifs also seen for endogenous citrullination in the rheumatoid joint. Highly bound peptides had multiple features predictive of disorder. IgG from CCP+RF+ subjects targeted citrulline-containing IgG-derived peptides.

Disordered antigens, which are frequently citrullinated, and common epitopes for ACPAs and RF are potentially unifying features for rheumatoid arthritis autoantibodies. This article is protected by copyright. All rights reserved.