Targeted Therapies in Psoriatic Arthritis-An Update.

Psoriatic arthritis (PsA) is a systemic inflammatory condition characterised by multiple clinical manifestations. Over the last decade, significant progress has been made in understanding the pathobiology of the disease. An expanded set of targeted therapies have emerged and have shown efficacy in PsA.

EULAR points to consider for minimal reporting requirements in synovial tissue research in rheumatology.

Background: Synovial tissue research has become widely developed in several rheumatology centres, however, large discrepancies exist in the way synovial tissue is handled and, more specifically, how data pertaining to biopsy procedure, quality check and experimental results are reported in the literature. This heterogeneity hampers the progress of research in this rapidly expanding field. In that context, under the umbrella of European Alliance of Associations for Rheumatology, we aimed at proposing points to consider (PtC) for minimal reporting requirements in synovial tissue research.

Loss of balance between protective and pro-inflammatory synovial tissue T-cell polyfunctionality predates clinical onset of rheumatoid arthritis.

Objectives: This study investigates pathogenic and protective polyfunctional T-cell responses in patient with rheumatoid arthritis (RA), individuals at risk (IAR) and healthy control (HC) synovial-tissue biopsies and identifies the presence of a novel population of pathogenic polyfunctional T-cells that are enriched in the RA joint prior to the development of clinical inflammation.

Methods: Pathway enrichment analysis of previously obtained RNAseq data of synovial biopsies from RA (n=118), IAR (n=20) and HC (n=44) was performed. Single-cell synovial tissue suspensions from RA (n=10), IAR (n=7) and HC (n=7) and paired peripheral blood mononuclear cells (PBMC) were stimulated in vitro and polyfunctional synovial T-cell subsets examined by flow cytometric analysis, simplified presentation of incredibly complex evaluations (SPICE) and FlowSom clustering.

Serum miRNA Signature in Rheumatoid Arthritis and "At-Risk Individuals".

Background: MicroRNAs (miRNAs) are small non-coding RNAs which have been implicated as potential biomarkers or therapeutic targets in autoimmune diseases. This study examines circulatory miRNAs in RA patients and further investigates if a serum miRNA signature precedes clinical manifestations of disease in arthralgia or "at-risk individuals".

Methods: Serum was collected from HC subjects (N = 20), RA patients (N = 50), and arthralgia subjects (N = 10), in addition to a subgroup of the RA patients post-methotrexate (MTX) (N = 18).

Arthroscopic Guided Synovial Biopsies.

Synovial tissue can be safely and reliably collected for research and clinical purposes using arthroscopy. This technique offers the obvious advantage of allowing direct visualization, and targeted biopsy of specific areas of interest within the joint, as well as for the collection of tissue which will include a lining layer. Much has been learnt by studying the synovium retrieved using this technique concerning the pathobiology of inflammatory arthritis.

Correction to: Standardisation of synovial biopsy analyses in rheumatic diseases: a consensus of the EULAR Synovitis and OMERACT Synovial Tissue Biopsy Groups.

Following publication of the original article [1], the authors reported an error in the spelling of the ninth author's name.

Enriched Cd141+ DCs in the joint are transcriptionally distinct, activated, and contribute to joint pathogenesis.

CD141+ DC are implicated in antiviral and antitumor immunity. However, mechanistic studies in autoimmune disease are limited. This is the first study to our knowledge examining CD141+ DC in autoimmune disease, specifically inflammatory arthritis (IA).

Standardisation of synovial biopsy analyses in rheumatic diseases: a consensus of the EULAR Synovitis and OMERACT Synovial Tissue Biopsy Groups.

Background: The aim of this global collaboration was to develop a consensual set of items for the analysis of synovial biopsies in clinical practice and translational research through the EULAR Synovitis Study Group (ESSG) and OMERACT Synovial Tissue Biopsy Group.

Methods: Participants were consulted through a modified Delphi method. Three sequential rounds occurred over 12 months.

The Utility and Limitations of CRP, ESR and DAS28-CRP in Appraising Disease Activity in Rheumatoid Arthritis.

Identifying and quantifying inflammatory disease activity in rheumatoid arthritis remains a challenge. Many studies have suggested that a large proportion of patients may have active inflammation, but normal inflammatory markers. Although various disease activity scores have been validated, most rely to a large degree on biomarkers such as CRP and ESR.

Oxidative stress impairs energy metabolism in primary cells and synovial tissue of patients with rheumatoid arthritis.

Background: In this study, we examined the effect of oxidative stress on cellular energy metabolism and pro-angiogenic/pro-inflammatory mechanisms of primary rheumatoid arthritis synovial fibroblast cells (RASFC) and human umbilical vein endothelial cells (HUVEC).

Methods: Primary RASFC and HUVEC were cultured with the oxidative stress inducer 4-hydroxy-2-nonenal (4-HNE), and extracellular acidification rate, oxygen consumption rate, mitochondrial function and pro-angiogenic/pro-inflammatory mechanisms were assessed using the Seahorse analyser, complex I-V activity assays, random mutation mitochondrial capture assays, enzyme-linked immunosorbent assays and functional assays, including angiogenic tube formation, migration and invasion. Expression of angiogenic growth factors in synovial tissue (ST) was assessed by IHC in patients with rheumatoid arthritis (RA) undergoing arthroscopy before and after administration of tumour necrosis factor inhibitors (TNFi).

JAK/STAT Blockade Alters Synovial Bioenergetics, Mitochondrial Function, and Proinflammatory Mediators in Rheumatoid Arthritis.

Objective: To examine the effects of tofacitinib on metabolic activity, mitochondrial function, and proinflammatory mechanisms in rheumatoid arthritis (RA).

Methods: Ex vivo RA synovial explants and primary RA synovial fibroblasts (RASFs) were cultured with 1 μM tofacitinib. RASF bioenergetics were assessed using an XF24 analyzer, and key metabolic genes were assessed by reverse transcription-polymerase chain reaction (RT-PCR) analysis.

Knee joint synovitis: study of correlations and diagnostic performances of ultrasonography compared with histopathology.

Objectives: Ultrasonography (US) is a fast, available and low-cost imaging tool used for detecting knee synovitis. Our aims were to assess the relationship between US and histology findings in appraising levels of inflammation and vascularity in the knee joint in subjects with inflammatory arthropathies; to determine whether differences exist in the appraisal between varying knee compartments and to compare US performances compared with gold standard histology for knee synovitis detection.

Methods: Subjects with actively inflamed knee joint having crystal arthropathies, rheumatoid arthritis, psoriatic arthritis or ostoearthritis were prospectively recruited from rheumatology clinics after giving their written consent between May and October 2015.

Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression.

Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA.

Corrigendum: Synovial tissue research: a state-of-the-art review.

This corrects the article DOI: 10.1038/nrrheum.2017.

Synovial tissue research: a state-of-the-art review.

This corrects the article DOI: 10.1038/nrrheum.2017.

Synovial Immunophenotype and Anti-Citrullinated Peptide Antibodies in Rheumatoid Arthritis Patients: Relationship to Treatment Response and Radiologic Prognosis.

Objective: Serum anti-citrullinated peptide antibodies (ACPAs) may be present before the development of rheumatoid arthritis (RA) and may be predictive of more severe, erosive disease. This study was undertaken to examine the synovial tissue immunophenotype according to ACPA status in patients with RA, as well as the response to treatment and erosion status.

Methods: Consecutive RA patients were prospectively recruited and underwent clinical and serologic assessments before and after treatment.

Synovial tissue research: a state-of-the-art review.

The synovium is the major target tissue of inflammatory arthritides such as rheumatoid arthritis. The study of synovial tissue has advanced considerably throughout the past few decades from arthroplasty and blind needle biopsy to the use of arthroscopic and ultrasonographic technologies that enable easier visualization and improve the reliability of synovial biopsies. Rapid progress has been made in using synovial tissue to study disease pathogenesis, to stratify patients, to discover biomarkers and novel targets, and to validate therapies, and this progress has been facilitated by increasingly diverse and sophisticated analytical and technological approaches.

Lesson of the month 1: Septic arthritis with normal acute phase reactants and white cell count in a patient receiving tocilizumab.

Septic arthritis represents 8-27% of cases of monoarthritis presenting to the emergency department. Tocilizumab is an interleukin-6 blocking monoclonal antibody with the mechanistic potential to interfere with the body's normal inflammatory response to an infectious insult. We present a case of septic arthritis with a normal white cell count, C-reactive protein, erythrocyte sedimentation rate and fibrinogen in a patient treated with tocilizumab.

Cellular and molecular perspectives in rheumatoid arthritis.

Synovial immunopathology in rheumatoid arthritis is complex involving both resident and infiltrating cells. The synovial tissue undergoes significant neovascularization, facilitating an influx of lymphocytes and monocytes that transform a typically acellular loose areolar membrane into an invasive tumour-like pannus. The microvasculature proliferates to form straight regularly-branching vessels; however, they are highly dysfunctional resulting in reduced oxygen supply and a hypoxic microenvironment.

CD40L-Dependent Pathway Is Active at Various Stages of Rheumatoid Arthritis Disease Progression.

The inflammatory CD40-CD40L pathway is implicated in various autoimmune diseases, but the activity status of this pathway in various stages of rheumatoid arthritis (RA) progression is unknown. In this study, we used gene signatures of CD40L stimulation derived from human immature dendritic cells and naive B cells to assess the expression of CD40-downstream genes in synovial tissues from anti-citrullinated protein Ab-positive arthralgia, undifferentiated arthritis (UA), early RA, and established RA cohorts in comparison with healthy donors. Interestingly, the expression of and active full-length was increased in the disease tissues, whereas that of a dominant-negative isoform was decreased.