The Many Faces of Interleukin-6: The Role of IL-6 in Inflammation, Vasculopathy, and Fibrosis in Systemic Sclerosis

Interleukin-6 is currently attracting significant interest as a potential therapeutic target in systemic sclerosis (SSc). In this paper, the biology of interleukin-6 is reviewed, and the evidence for interleukin-6 dysregulation in SSc is explored. The role of inteleukin-6 classical and trans signalling pathways in SSc relevant phenomena such as chronic inflammation, autoimmunity, endothelial cell dysfunction, and fibrogenesis is discussed. The existing evidence that interventions designed to block interleukin-6 signalling are of therapeutic relevance in SSc is evaluated

Fibromyalgia in Behçet's disease: a narrative review.

IntroductionFibromyalgia is characterised by chronic widespread pain and tenderness. It has often been reported to occur concomitantly with chronic rheumatological conditions. Behçet's disease is a chronic relapsing, multisystem, autoinflammatory disease. There is only limited understanding of a potential relationship between fibromyalgia and Behçet's disease.AimGiven the potential detrimental influence of pain on the outcome of chronic disease, the aim of this narrative review is to gain an understanding of the incidence and presentation of fibromyalgia in Behçet's disease.MethodsElectronic databases Scopus, Medline, PubMed and UpToDate were searched.ResultsA total of 269 studies were identified, and limitations and exclusion/inclusion criteria were applied to ensure accurate and comparable selection of studies; four studies were selected. All cases were assessed for the presence of fibromyalgia according to the 1990 or 2010 diagnostic criteria of the American College of Rheumatology, with Behçet's disease diagnosed according to the International Study Group (ISG) for Behçet's disease criteria. A higher prevalence of fibromyalgia (5.7-37.1%) was reported in Behçet's disease compared to that of the general population (2.9-4.7%).DiscussionWhile an increased prevalence of fibromyalgia was found in patients with Behçet's disease, this needs to be considered within the context of limited available evidence. The potential impact of these conditions on the disease activity of each other is not clear and may require a prospective study.ConclusionFibromyalgia appears to be more prevalent in those with Behçet's disease than would be expected in the overall population. Significance: This review provides some evidence that fibromyalgia is more prevalent in those with Behçet's disease. To ensure appropriate patient treatment choices, it is important that both conditions are diagnosed where they co-exist

Depression and anxiety symptoms at TNF inhibitor initiation are associated with impaired treatment response in axial spondyloarthritis

Acknowledgment We are grateful to Professor Gary Macfarlane for commenting on the manuscript. We are grateful to the staff of the BSRBR-AS register and to the recruiting staff at the clinical centres, details of which are available at: www.abdn.ac.uk/bsrbr-as. We also thank Dr Lewis Carpenter for suggesting splines for modelling time. Contribution: SSZ analysed the data and wrote the manuscript with significant input from all co- authors. GTJ is the Deputy Chief Investigator on BSRBR-AS and designed the study and oversaw its conduct. In the current project they discussed results and provided input into drafts of the manuscript. Funding: The BSRBR-AS is funded by the British Society for Rheumatology (BSR) who have received funding for this from Pfizer, AbbVie and UCB. These companies receive advance copies of manuscripts for comments. They have no input in determining the topics for analysis or work involved in undertaking it.Peer reviewedPublisher PD

Type I Interferon regulates cytokine-delayed neutrophil apoptosis, reactive oxygen species production and chemokine expression via activation of p38 MAPK

ABSTRACTInterferons (IFNs) are key regulators of a number of inflammatory conditions in which neutrophils play an important role in pathology, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), where Type I IFNs are implicated in disease pathology. However, IFNs are usually generated in vivo together with other cytokines that also have immunoregulatory functions but such interactions are poorly-defined experimentally. We measured the effects of Type-I IFN (IFNα), elevated in both RA and SLE, on the functions of healthy neutrophils incubated in vitro in the absence and presence of pro-inflammatory cytokines typically elevated in inflammatory diseases (TNFα, GM-CSF). IFNα alone had no effect on neutrophil apoptosis, however it did abrogate the anti-apoptotic effect of GM-CSF (18h, p&lt; 0.01). The enhanced stabilty of the anti-apoptotic protein Mcl-1 and delayed activation of caspase activation normally regulated by GM-CSF were blocked by IFNα: this effect was mediated, in part, by activation of p38 MAPK, increased turnover of the anti-apoptotic protein Mcl-1 and cleavage of caspases. IFNα alone also primed ROS production alone and maintained the transient priming effect of TNF for up to 4h: it also down-regulated GM-CSF and TNFα-activated expression of CXCL1, CXCL2, CXCL3, CXCL8, CCL3 and CCL4, but in contrast increased the expression of CXCL10. These novel data identify complex regulatory signalling networks in which Type I IFNs profoundly alter the response of neutrophils to inflammatory cytokines. This is likely to have important consequences in vivo and may explain the complexity and heterogeneity of inflammatory diseases such as RA, in which multiple cytokine cascades have been activated.</jats:p

Comorbidity and response to TNF inhibitors in axial spondyloarthritis : longitudinal analysis of the BSRBR-AS

Acknowledgements: Funding: The BSRBR-AS is funded by the British Society for Rheumatology (BSR) who have received funding for this from Pfizer, AbbVie and UCB. These companies receive advance copies of manuscripts for comments. They have no input in determining the topics for analysis or work involved in undertaking it. Disclosures: The authors declare no conflicts of interest. Contribution: SSZ analysed the data and wrote the manuscript, with significant input from all coauthors. GJM and GTJ are Chief Investigator and Deputy Chief Investigator respectively on BSRBR-AS and designed the study and oversaw its conduct. In the current project they discussed results and provided input into drafts of the manuscript. Data availability: Data from the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis are available to external investigators, on reasonable request. For information on how to access data, see: http://www.rheumatology.org.uk. We are grateful to the staff of the BSRBR-AS register and to the recruiting staff at the clinical centres, details of which are available at: www.abdn.ac.uk/bsrbr-asPeer reviewedPublisher PD