Objectives. Reports on the regulation of neutrophil function by IL-6 are often conflicting. Therapeutic inhibition of IL-6 in RA is associated with occasional neutropenia, but the mechanisms underlying this observation are poorly understood. This study investigated interactions between IL-6, the anti-IL-6 receptor agent tocilizumab (TCZ) and neutrophils in vitro and in vivo. Methods. Neutrophils were isolated from healthy controls and incubated in vitro with pharmacologically relevant concentrations of IL-6 or TCZ. Neutrophils were also isolated from RA patients, including a cohort following TCZ therapy. Apoptosis was measured by annexin V/propidium iodide (PI) flow cytometry; phagocytosis was measured by incubating apoptotic neutrophils with THP-1-derived macrophages; chemotaxis was measured using cell migration through hanging-cell inserts towards IL-8 and cell surface proteins, including adhesion molecules CD11b (α_Mβ₂ integrin) and CD62L (L-selectin) were measured by flow cytometry. Results. IL-6 (10–100 ng/ml) did not affect the rate of neutrophil apoptosis, priming of the respiratory burst or adhesion molecule expression nor act as a neutrophil chemoattractant. However, IL-6 enhanced signal transducer and activator of transcription 3 (STAT3) activation and neutrophil migration towards IL-8. TCZ in vitro did not induce apoptosis or phagocytosis of neutrophils, nor did it have a significant effect upon apoptosis or cell surface molecule expression. Neutrophil functions in ex vivo neutrophils from RA patients receiving TCZ treatment were unaffected. Conclusion. Therapeutic blockade of IL-6, while inducing a transient neutropenia, does not directly affect neutrophil functions associated with host defence. TCZ-associated neutropenia cannot be explained by direct induction of apoptosis by TCZ, induction of apoptosis following depletion of IL-6, nor increased phagocytosis of neutrophils.

Objective. The aim of this study was to use whole transcriptome sequencing (RNA-Seq) of RA neutrophils to identify pre-therapy gene expression signatures that correlate with disease activity or response to TNF inhibitor (TNFi) therapy. Methods. Neutrophils were isolated from the venous blood of RA patients (n = 20) pre-TNFi therapy and from healthy controls (n = 6). RNA was poly(A) selected and sequenced on the Illumina HiSeq 2000 platform. Reads were mapped to the human genome (hg19) using TopHat and differential expression analysis was carried out using edgeR (5% false discovery rate). Signalling pathway analysis was carried out using Ingenuity Pathway Analysis (IPA) software. IFN signalling was confirmed by western blotting for phosphorylated signal transducer and activator of transcription (STAT) proteins. Response to TNFi was measured at 12 weeks using change in the 28-item DAS (DAS28). Results. Pathway analysis with IPA predicted activation of IFN signalling in RA neutrophils, identifying 178 IFN-response genes regulated by IFN-α, IFN-β or IFN-γ (P < 0.01). IPA also predicted activation of STAT1, STAT2 and STAT3 transcription factors in RA neutrophils (P < 0.01), which was confirmed by western blotting. Expression of IFN-response genes was heterogeneous and patients could be categorized as IFN-high or IFN-low. Patients in the IFN-high group achieved a better response to TNFi therapy [ΔDAS28, P = 0.05, odds ratio (OR) 1.4 (95% CI 1.005, 1.950)] than patients in the IFN-low group. The level of expression of IFN-response genes (IFN score) predicted a good response [European League Against Rheumatism (EULAR) criteria] to TNFi using receiver operating characteristic curve analysis (area under the curve 0.76). Conclusion. IFN-response genes are significantly up-regulated in RA neutrophils compared with healthy controls. Higher IFN-response gene expression in RA neutrophils correlates with a good response to TNFi therapy.

Etanercept was the first specific anticytokine therapy approved for the treatment of rheumatoid arthritis (RA). Its clinical efficacy and safety has been demonstrated by several clinical trials in early as well as established disease. Etanercept, along with other TNF inhibitors, have revolutionized management of RA and dramatically improved disease activity, function, quality of life and mortality for these patients. It is structurally distinct from other TNF inhibitors and thus has desirable profiles for immunogenicity, drug survival and infection rate. With the increasing number of etanercept biosimilars, there will likely be a resurgence of their prescription. This article reviews the pharmacology, efficacy and safety of the etanercept reference product, and its biosimilars, in the context of RA treatment.

Purpose of Review Biosimilars of the reference biologic therapeutics infliximab, etanercept, adalimumab, and rituximab are entering the market. Clinical and real-world data on the effects of reference → biosimilar switching are limited. This review was carried out to assess the current body of switching data. Recent Findings Fifty-three switching studies were identified. Infliximab publications covered CT-P13 (25 studies), SB2 (1), infliximab NK (1), and unspecified infliximab biosimilars (2). Etanercept publications covered SB4 (2) and GP2015 (2). Adalimumab publications covered ABP 501 (2) and SB5 (1). Rituximab publications covered CT-P10 (1). Efficacy and safety data generally showed no differences between patients who switched treatments versus those who did not. No differences were seen pre- and post-switch. Immunogenicity data were presented in 19/37 (51%) studies. Summary Additional data from switching studies of these therapies are still required, as is continuing pharma-covigilance. Switching should remain a case-by-case clinical decision made by the physician and patient on an individual basis supported by scientific evidence.

Background. Natural killer (NK) cells play an important role in several animal models of autoimmunity by modulating T‐cell responses, but it is unclear whether human NK cells have similar functions. Methods. We characterized the phenotype of NK cells in synovial fluid (SF) and peripheral blood (PB) of patients with rheumatoid arthritis (RA) and in healthy control subjects using flow cytometry and quantitative PCR. Results. The proportions of NK cells in PB and SF of RA patients were not significantly different from those in healthy PB. However, the SF NK cell phenotype was strikingly different, with increased CD94 and CD56 densities and greatly reduced proportions of cells expressing CD158a/b. These cells also had reduced mRNAs coding for CD158a/b and low perforin levels compared with RA PB and healthy PB NK cells. Conclusions. We identified a novel phenotype of SF NK cells that is of potential significance in RA. Experiments are now under way to determine the function of these SF NK cells and their potential role in RA.

Musculoskeletal manifestations of the human immunodeficiency virus (HIV) have been described since the outset of the global HIV epidemic. Articular syndromes that have been described in association with HIV include HIV-associated arthropathy, seronegative spondyloarthropathies (SPA) (reactive arthritis, psoriatic arthritis (PsA) and undifferentiated SPA), rheumatoid arthritis (RA) and painful articular syndrome. We carried out a computer-assisted search of PubMed for the medical literature from January 1981 to January 2015 using the keywords HIV, acquired immune-deficiency syndrome, rheumatic manifestations, arthritis, spondyloarthropathy, anti-TNF and disease modifying antirheumatic drugs. Only English language literature was included and only studies involving adult human subjects were assessed. There are challenges in the management of inflammatory arthritis in patients who are HIV-positive, including difficulties in the assessment of disease activity and limited information on the safety of immunosuppressive drugs in these individuals. This review focuses on the clinical characteristics of the inflammatory articular syndromes that have been described in association with HIV infection and discusses the therapeutic options for these patients.