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The role of the gut microbiome in models of inflammatory and autoimmune disease is now well characterized. Renewed interest in the human microbiome and its metabolites, as well as notable advances in host mucosal immunology, has opened multiple avenues of research to potentially modulate inflammatory responses. The complexity and interdependence of these diet-microbe-metabolite-host interactions are rapidly being unraveled. Importantly, most of the progress in the field comes from new knowledge about the functional properties of these microorganisms in physiology and their effect in mucosal immunity and distal inflammation. This review summarizes the preclinical and clinical evidence on how dietary, probiotic, prebiotic, and microbiome based therapeutics affect our understanding of wellness and disease, particularly in autoimmunity.

Programmed death-1 (PD-1) is an inhibitory co-receptor that is highly expressed in T lymphocytes that has been shown to downregulate inflammatory responses in several inflammatory diseases including systemic lupus erythematosus and rheumatoid arthritis. Yet, the role of PD-1 in psoriatic arthritis (PsA) has not been studied. In order to fill this gap, we measured the expression levels of PD-1 in peripheral T cells from patients with active disease. Twenty patients and fifteen age-matched healthy control subjects were recruited. The percentage of CD3(+)PD-1(+) T cells was measured by flow cytometry. Despite normal concentration of peripheral T cells, the expression levels of PD-1 were significantly higher in patients compared to healthy controls. Interestingly, among the patients, the expression levels inversely correlated with disease activity measured by disease activity scores (DAS28). PD-1 expression levels strongly correlated with the number of tender and swollen joints, but not with C-reactive protein (CRP) levels or psoriasis area and severity index (PASI). Functionally, in vitro ligation of PD-1 receptor in PsA T cells inhibited interleukin-2 (IL-2) secretion, Akt phosphorylation, and Rap1 activation. These findings suggest that PD-1 might serve as a biomarker for disease activity in PsA and highlight the need for additional studies in order to establish the role of PD-1 in PsA pathogenesis.

Objective To characterize the diversity and taxonomic relative abundance of the gut microbiota in patients with never-treated, recent-onset psoriatic arthritis (PsA). Methods High-throughput 16S ribosomal RNA pyrosequencing was utilized to compare the community composition of gut microbiota in patients with PsA (n = 16), patients with psoriasis of the skin (n = 15), and healthy, matched control subjects (n = 17). Samples were further assessed for the presence and levels of fecal and serum secretory IgA (sIgA), proinflammatory proteins, and fatty acids. Results The gut microbiota observed in patients with PsA and patients with skin psoriasis was less diverse when compared to that in healthy controls. This could be attributed to the reduced presence of several taxa. Samples from both patient groups showed a relative decrease in abundance of Coprococcus species, while samples from PsA patients were also characterized by a significant reduction in Akkermansia, Ruminococcus, and Pseudobutyrivibrio. Supernatants of fecal samples from PsA patients revealed an increase in sIgA levels and decrease in RANKL levels. Analysis of fatty acids revealed low fecal quantities of hexanoate and heptanoate in both patients with PsA and patients with psoriasis. Conclusion Patients with PsA and patients with skin psoriasis had a lower relative abundance of multiple intestinal bacteria. Although some genera were concomitantly decreased in both conditions, PsA samples had a lower abundance of reportedly beneficial taxa. This gut microbiota profile in PsA was similar to that previously described in patients with inflammatory bowel disease and was associated with changes in specific inflammatory proteins unique to this group, and distinct from that in patients with skin psoriasis and healthy controls. Thus, the role of the gut microbiome in the continuum of psoriasis–PsA pathogenesis and the associated immune response merits further study.

Microbes have coevolved with their human hosts for millions of years and are vital to their normal development and homoeostasis. It is now clear that there is direct and indirect cross talk between the microbiome and host immune responses. However, the exact mechanisms for this microbial influence in disease pathogenesis remain elusive and are now a major research focus.

Background Intestinal microbiota have been associated with psoriatic and rheumatoid arthritis. One of the major effects of microbiota is the induction of mucosal T helper 17 (Th17) cells. We therefore reasoned that the efficiacy of Th17-targeted therapies in arthritis may depend on the host microbiota. Previous studies focused on the role of the cytokine interleukin-17A (IL-17), rather than Th17 cells, by using IL-17 inhibitors or IL-17-deficient mice. Therefore, the role of Th17 cells, which produce multiple pro-inflammatory mediators in addition to IL-17, is not yet fully understood. Objectives The aim of this study was to determine the role of Th17 cells, beyond the cytokine IL-17, in arthritis, and to investigate whether Th17 cells are differentially involved in arthritis depending on the microbiota present. Methods We established conditional Th17-deficient mice, which exhibit a CD4-Cre-induced floxing of a part of the Rorc allele that encodes the Th17 master regulator RORγt. We compared the development of collagen-induced arthritis in Th17-deficient (CD4-Cre+ Rorcflox/flox) and -sufficient (CD4-Cre- Rorcflox/flox) littermate mice, either colonized with known Th17 cell inducers segmented filamentous bacteria (SFB) or harboring the SFB-free Jackson microbiota. The abundance of Th1 and Th17 cells and the production of IL-17, IFNγ and GM-CSF were quantified by flow cytometry and multiplex cytokine assay. Results CD4-Cre+ Rorcflox/flox mice had significantly lower Th17, but similar Th1 cell abundance, in intestinal lamina propria compared with Cre- littermate controls. Surprisingly, the total amount of IL-17A production by all lamina propria cells during arthritis was rather increased in Th17-deficient mice, with CD8+ T cells and Gr1+ neutrophils being the main alternative sources of IL-17. Despite this increased total IL-17 levels, conditional Th17-deficient mice developed a less severe arthritis compared with Th17-sufficient mice when intestinal microbiota comprised SFB. This suggests a role for Th17 cells in inflammatory arthritis distinct from IL-17. Accordingly, synovial inflammation, cartilage destruction and proteoglycan depletion were reduced in SFB-colonized Th17-deficient mice. While the production of IL-17 by joint-draining lymph node cells stimulated with PMA and ionomycin was similar between Th17-sufficient and –deficient mice, cells from the latter group produced significantly less IL-17 upon antigen-specific stimulation with type II collagen. Furthermore, the production of GM-CSF, another Th17 cell-derived cytokine, was significantly lower in the lymph nodes of Th17-deficient mice, an effect associated with the protection against arthritis. Importantly, substitution of the intestinal microbiota with SFB-free Jackson microbiota resulted in the loss of Th17 cell dependency of arthritis as Th17-sufficient and –deficient mice showed similar disease progression under this condition. Conclusions These data suggest that Th17 cells may mediate inflammatory arthritis partly through IL-17-independent mechanisms. Our observations also suggest that the involvement of Th17 cells in arthritis depends on the microbiota subset present in the host. Therefore, a microbiome-guided stratification of rheumatoid or psoriatic arthritis patients might improve the efficacy of Th17 (or IL-17)-targeted therapies. Disclosure of Interest None declared

Background The composition of intestinal microbiota is perturbed in patients with new-onset rheumatoid arthritis (RA) and those with chronic RA. However, it is not known whether the changes in the intestinal microbiome precede the development of arthritis or are rather a consequence of the inflammatory processes. Furthermore, while both germ-free condition and administration of oral antibiotics prevent arthritis in mice, it is unclear whether modulation of the intestinal microbiota after the onset of arthritis may still suppress the disease. Objectives We aimed to assess potential alterations of the intestinal microbiome in the preclinical phase of inflammatory arthritis, and to determine the efficacy of microbiota modulations in the treatment of established disease in mice. Methods We sequenced fecal bacterial 16S rRNA to define the intestinal microbiome in mice before immunization with collagen and 21 days later before the booster injection for the induction of collagen-induced arthritis (CIA). To assess the efficacy of microbiota modulation during arthritis, mice with ongoing CIA were treated orally by a broad-spectrum antibiotic cocktail for one week to partially eliminate the intestinal microbiota. T cell differentiation and production of cytokines in intestinal lamina propria and joint-draining lymph nodes were assessed by flow cytometry and Luminex. Arthritis was assessed macroscopically and by histology. Serum-transfer arthritis induced by intraperitoneal injections of arthritogenic K/BxN mouse serum was used as a control, T cell-independent, model. Results The preclinical phase of inflammatory arthritis in mice was characterized by marked changes in the intestinal microbiome, represented by a significant increase of the phylum Bacteroidetes and a decrease of Firmicutes and Proteobacteria. Among the most abundant bacterial families, S24–7 and Staphylococcaceae were expanded, whereas Lachnospiraceae were reduced during the immune priming phase of CIA. Several operational taxonomic units associated with S24–7 family increased, while those assigned to Lachnospiraceae and Ruminococcaceae decreased in the intestinal microbiota before the clinical onset of arthritis. The abundance of intestinal lamina propria Th17 cells significantly correlated with the severity of CIA; however, intestinal Th1 cells were not correlated with the disease. Elimination of intestinal microbiota in mice with ongoing CIA specifically suppressed intestinal Th17 cell differentiation without affecting Th1 and Treg cells. Importantly, elimination of intestinal microbiota suppressed Th17 cell differentiation and IL-17 production in joint-draining lymph nodes, and reduced the severity of established CIA. In contrast, the T cell-independent serum-transfer arthritis was not affected by this strategy. Conclusions These observations suggest that perturbations of the intestinal microbiome may precede the development of inflammatory arthritis. Similar studies are warranted in human pre-RA or at-risk individuals to shed light on the functional role of the microbiome in the development of RA. Our studies also suggest that modulation of the intestinal microbiota after the onset arthritis may still provide opportunities to treat inflammatory arthritis. Disclosure of Interest None declared

Background/objectives Both germ-free condition and administration of oral antibiotics before the onset of arthritis modulate T cell differentiation and attenuate arthritis in mice. However, it is not known whether and how the modulation of intestinal microbiota after the onset of arthritis may influence the disease. Here, we investigated the involvement of commensal intestinal microbiota in the progression of established arthritis in both T cell-dependent and -independent mouse models. Materials and methods Mice with established collagen-induced arthritis (CIA) as well as mice with K/BxN serum-transfer arthritis were treated orally with broad-spectrum antibiotics for one week to partially eliminate intestinal microbiota. 16S rRNA gene high-throughput sequencing was performed to assess the effect of arthritis and antibiotic treatment on the gut microbiota composition. Arthritis was assessed macroscopically and by histology. Differentiation of Th1, Th17 and regulatory T (Treg) cells and production of their prototypic cytokines in intestinal lamina propria and joint-draining lymph nodes were assessed by flow cytometry and Luminex cytokine array. Results Induction of arthritis as such resulted in significant alterations in the gut microbiota. Antibiotic treatment of CIA mice eliminated the majority of the gut microbiota, while the microbiota composition of control mice remained relatively stable. Partial elimination of intestinal microbiota during ongoing CIA specifically suppressed intestinal Th17 cell differentiation without affecting Th1 and Treg cells. Accordingly, production of IL-17, but not IFNγ, IL-4 and IL-10, by lamina propria lymphocytes was significantly diminished in antibiotic-treated mice. Importantly, elimination of intestinal microbiota resulted in suppressed Th17 cell differentiation in joint-draining lymph nodes and reduced the severity of established CIA. In contrast, antibiotic treatment did not influence disease severity in the T cell-independent K/BxN serum-transfer arthritis. Intriguingly, the abundance of intestinal Th17 cells strongly correlated with the severity of arthritis in the CIA mice. However, elimination of intestinal microbiota after disease onset did not affect the development of anti-collagen type II auto-antibodies. Conclusion These observations suggest that modulation of commensal intestinal microbiota during established arthritis specifically suppresses Th17 differentiation and dampens T cell-mediated arthritic processes. Our study supports the notion that inflammatory signals provided by the gut microbiota continue to promote arthritis after its onset.

Perturbations of the intestinal microbiome have been observed in patients with new-onset and chronic autoimmune inflammatory arthritis. However, it is currently unknown whether these alterations precede the development of arthritis or are rather a consequence of disease. Modulation of intestinal microbiota by oral antibiotics or germ-free condition can prevent arthritis in mice. Yet, the therapeutic potential of modulation of the microbiota after the onset of arthritis is not well characterized. We here show that the intestinal microbial community undergoes marked changes in the preclinical phase of collagen induced arthritis (CIA). The abundance of the phylum Bacteroidetes, specifically families S24-7 and Bacteroidaceae was reduced, whereas Firmicutes and Proteobacteria, such as Ruminococcaceae, Lachnospiraceae and Desulfovibrinocaceae, were expanded during the immune-priming phase of arthritis. In addition, we found that the abundance of lamina propria Th17, but not Th1, cells is highly correlated with the severity of arthritis. Elimination of the intestinal microbiota during established arthritis specifically reduced intestinal Th17 cells and attenuated arthritis. These effects were associated with reduced serum amyloid A expression in ileum and synovial tissue. Our observations suggest that intestinal microbiota perturbations precede arthritis, and that modulation of the intestinal microbiota after the onset of arthritis may offer therapeutic opportunities.

Rho-associated kinase 2 (ROCK2) regulates the secretion of proinflammatory cytokines and the development of autoimmunity in mice. Data from a phase 1 clinical trial demonstrate that oral administration of KD025, a selective ROCK2 inhibitor, to healthy human subjects down-regulates the ability of T cells to secrete IL-21 and IL-17 by 90% and 60%, respectively, but not IFN-γ in response to T-cell receptor stimulation in vitro. Pharmacological inhibition with KD025 or siRNA-mediated inhibition of ROCK2, but not ROCK1, significantly diminished STAT3 phosphorylation and binding to IL-17 and IL-21 promoters and reduced IFN regulatory factor 4 and nuclear hormone RAR-related orphan receptor γt protein levels in T cells derived from healthy subjects or rheumatoid arthritis patients. Simultaneously, treatment with KD025 also promotes the suppressive function of regulatory T cells through up-regulation of STAT5 phosphorylation and positive regulation of forkhead box p3 expression. The administration of KD025 in vivo down-regulates the progression of collagen-induced arthritis in mice via targeting of the Th17-mediated pathway. Thus, ROCK2 signaling appears to be instrumental in regulating the balance between proinflammatory and regulatory T-cell subsets. Targeting of ROCK2 in man may therefore restore disrupted immune homeostasis and have a role in the treatment of autoimmunity.

Purpose of review Since the early 1900s, the role of periodontal disease in the pathogenesis of rheumatoid arthritis has been a matter of intense research. The last decade has witnessed many advances supporting a link between periodontitis, the presence of specific bacterial species (i.e. Porphyromonas gingivalis) and their effects in immune response. This review will examine available evidence on the individuals. Recent findings Epidemiological studies have stressed the commonalities shared by periodontal disease and rheumatoid arthritis. Many groups have focused their attention toward understanding the periodontal microbiota and its alterations in states of health and disease. The presence of circulating antibodies against periodontopathic bacteria and associated inflammatory response has been found in both rheumatoid arthritis (RA) patients and individuals at-risk for disease development. Most recently, the periodontal microbiota of smokers and patients with RA has been elucidated, revealing profound changes in the bacterial communities compared with those of healthy controls. This has led to several small clinical trials of progressive disease treatment as adjuvant for disease-modifying therapy in RA. Summary Smoking and periodontal disease are emerging risk factors for the development of RA. Epidemiological, clinical, and basic research has further strengthened this association, pointing toward changes in the oral microbiota as possible contributors to systemic inflammation and arthritis.

Despite the progress toward understanding the molecular pathogenesis of rheumatoid arthritis (RA), its cause remains elusive. Genes are important but rather insufficient to explain the majority of RA cases. This review describes the novel data supporting the microbiome and its interactions with the human host as potential en('in')vironmental factors in RA pathogenesis.Animal models of inflammatory arthritis have shown that the presence of bacteria in mucosal surfaces is sufficient to alter local and systemic host immune responses and elicit joint inflammation. Human RA studies have focused on three mucosal sites: the gut, the gingiva, and the respiratory tree. The oral microbiome, and specifically Porphyromonas gingivalis, has long been implicated. Novel sequencing technologies have allowed investigations into the role of the gut microbiome in the development of autoimmune arthritis. Most recently, the pulmonary parenchyma has also been described as yet another possible mucosal site of initiation of autoimmunity in RA.Emerging data implicate the microbiome in RA pathogenesis. Mucosal sites exposed to a high load of bacterial antigens--such as the periodontium, lung, and gut--may represent the initial site of autoimmune generation. If validated, these findings could lead to the discovery of potential biomarkers and therapeutic approaches in the preclinical and clinical phases of RA.

The etiopathogenesis of chronic, rheumatic autoimmune disorders has been the focus of intense research since their initial literary description. Despite much scientific iteration, the current hypothesis postulates that the natural history of most such diseases is complex and multifactorial. Ultimately, it is thought that both genetic factors (including epigenetic) and environmental influences determine the fate of predisposed subjects, who then develop clinically evident disease. The modern notion that autoimmune arthritides are the result of polygenic interactions dates back to the mid-1970s when it was shown that HLA-B27 conferred a high risk for classic ankylosing spondylitis (AS)1, followed by the description of the shared epitope hypothesis in 1987, which posited that HLA class II alleles, particularly DR-β1, conferred higher risk for the development of rheumatoid arthritis (RA)2. This, along with the advent of the Human Genome Project and the upsurge of genome-wide association studies, had led to an overly optimistic and, arguably, reductionist understanding of the etiology of inflammatory arthropathies. The last 3 decades have seen an ever-expanding use of high-throughput DNA sequencing by multiple groups in a quest to ascribe risk-alleles to the various autoimmune and rheumatic syndromes. This effort has resulted in, among other advances, the identification of many HLA and non-HLA risk alleles associated with disease and the emergence of a functional genomics approach to discovery and validation of immune pathways and molecular mechanisms implicated in the pathogenesis …

Item does not contain fulltext The role of the gut microbiome in animal models of inflammatory and autoimmune disease is now well established. The human gut microbiome is currently being studied as a potential modulator of the immune response in rheumatic disorders. However, the vastness and complexity of this host-microorganism interaction is likely to go well beyond taxonomic, correlative observations. In fact, most advances in the field relate to the functional and metabolic capabilities of these microorganisms and their influence on mucosal immunity and systemic inflammation. An intricate relationship between the microbiome and the diet of the host is now fully recognized, with the microbiota having an important role in the degradation of polysaccharides into active metabolites. This Review summarizes the current knowledge on the metabolic role of the microbiota in health and rheumatic disease, including the advances in pharmacomicrobiomics and its potential use in diagnostics, therapeutics and personalized medicine.

Inheriting the wrong genes and eating the wrong food (ie, gluten) are necessary for celiac disease to develop, but are not enough by themselves. Something else must be contributing, and evidence is pointing to the mix of bacteria that make our guts their home, collectively called the microbiome.

Rheumatoid arthritis (RA) is a chronic, destructive, autoimmune disorder characterized by autoantibody production and predilection for the joints that can lead to accelerated morbidity, mortality, and disability [1]. Current understanding of RA pathogenesis posits that a combination of host predisposition and risk factors is most likely required for the initiation and sustainability of the inflammatory process. However, the exact combination of factors and the precise timing for clinical manifestations are still insufficiently understood [2]. Mounting evidence suggests that environmental risk factors such as commensal and infectious microbiota may contribute to RA in patients with genetic susceptibility [3]. New findings suggest that germ-free mice, lacking all microbiota, are resistant to development of spontaneous autoimmune arthritis [4]. Intriguingly, recent evidence suggests that, in the right genetic background [5], the presence of certain predisposing factors (i.e., periodontitis (PD) and smoking) [6–9] along with serological markers (i.e., autoantibodies and proinflammatory cytokines) may predict the emergence of RA [10].

Background Airway abnormalities and lung tissue citrullination are found in both rheumatoid arthritis (RA) patients and individuals at-risk for disease development. This suggests the possibility that the lung could be a site of autoimmunity generation in RA, perhaps in response to microbiota changes. We therefore sought to test whether the RA lung microbiome contains distinct taxonomic features associated with local and/or systemic autoimmunity. Methods 16S rRNA gene high-throughput sequencing was utilized to compare the bacterial community composition of bronchoalveolar lavage fluid (BAL) in patients with early, disease-modifying anti-rheumatic drugs (DMARD)-naïve RA, patients with lung sarcoidosis, and healthy control subjects. Samples were further assessed for the presence and levels of anti-citrullinated peptide antibodies (including fine specificities) in both BAL and serum. Results The BAL microbiota of RA patients was significantly less diverse and abundant when compared to healthy controls, but similar to sarcoidosis patients. This distal airway dysbiosis was attributed to the reduced presence of several genus (i.e., Actynomyces and Burkhordelia) as well as reported periodontopathic taxa, including Treponema, Prevotella, and Porphyromonas. While multiple clades correlated with local and systemic levels of autoantibodies, the genus Pseudonocardia and various related OTUs were the only taxa overrepresented in RA BAL and correlated with higher disease activity and erosions. Conclusions Distal airway dysbiosis is present in untreated early RA and similar to that detected in sarcoidosis lung inflammation. This community perturbation, which correlates with local and systemic autoimmune/inflammatory changes, may potentially drive initiation of RA in a proportion of cases. Electronic supplementary material The online version of this article (doi:10.1186/s40168-016-0206-x) contains supplementary material, which is available to authorized users.

Optimal management of patients with both psoriasis and psoriatic arthritis (PsA) necessitates collaboration among dermatologists and rheumatologists. In this manuscript, we discuss challenges and opportunities for dual care models for patients with psoriasis and PsA and the results of a survey of combined clinics based in North America.

Because the mechanisms of Helicobacter pylori-induced gastric injury are incompletely understood, we examined the hypothesis that H. pylori induces matrix metalloproteinase-1 (MMP-1) secretion, with potential to disrupt gastric stroma. We further tested the role of CagA, an H. pylori virulence factor, in MMP-1 secretion. Co-incubation of AGS cells with Tx30a, an H. pylori strain lacking the cagA virulence gene, stimulated MMP-1 secretion, confirming cagA-independent secretion. Co-incubation with strain 147C (cagA(+)) resulted in CagA translocation into AGS cells and increased MMP-1 secretion relative to Tx30a. Transfection of cells with the recombinant 147C cagA gene also induced MMP-1 secretion, indicating that CagA can independently stimulate MMP-1 secretion. Co-incubation with strain 147A, containing a cagA gene that lacks an EPIYA tyrosine phosphorylation motif, as well as transfection with 147A cagA, yielded an MMP-1 secretion intermediate between no treatment and 147C, indicating that CagA tyrosine phosphorylation regulates cellular signaling in this model system. H. pylori induced activation of the MAP kinase ERK, with CagA-independent (early) and dependent (later) components. MEK inhibitors UO126 and PD98059 inhibited both CagA-independent and -dependent MMP-1 secretion, whereas p38 inhibition enhanced MMP-1 secretion and ERK activation, suggesting p38 negative regulation of MMP-1 and ERK. These data indicate H. pylori effects on host epithelial MMP-1 expression via ERK, with p38 playing a potential regulatory role.

The human microbiome, which represents the total collection of microorganisms (and their genes) inhabiting the human body, has increasingly been recognized as a potential key factor in the development of autoimmune disease. Multiple studies suggest that the microbiome has significant influence on immune homeostasis, while disruptions in local microbiome composition can result in a heightened systemic inflammatory response. The intestinal microbiome, in particular, harbors the densest assembly of bacteria and appears to influence the immune system in the context of inflammatory arthropathies. Although studies are still sparse, this review will examine the role of the microbiome in the pathogenesis of spondyloarthritis (SpA), particularly in enteropathic arthritis (EA), reactive arthritis (ReA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA).

To characterize the diversity and taxonomic relative abundance of the gut microbiota in patients with never-treated, recent-onset psoriatic arthritis (PsA).High-throughput 16S ribosomal RNA pyrosequencing was utilized to compare the community composition of gut microbiota in patients with PsA (n = 16), patients with psoriasis of the skin (n = 15), and healthy, matched control subjects (n = 17). Samples were further assessed for the presence and levels of fecal and serum secretory IgA (sIgA), proinflammatory proteins, and fatty acids.The gut microbiota observed in patients with PsA and patients with skin psoriasis was less diverse when compared to that in healthy controls. This could be attributed to the reduced presence of several taxa. Samples from both patient groups showed a relative decrease in abundance of Coprococcus species, while samples from PsA patients were also characterized by a significant reduction in Akkermansia, Ruminococcus, and Pseudobutyrivibrio. Supernatants of fecal samples from PsA patients revealed an increase in sIgA levels and decrease in RANKL levels. Analysis of fatty acids revealed low fecal quantities of hexanoate and heptanoate in both patients with PsA and patients with psoriasis.Patients with PsA and patients with skin psoriasis had a lower relative abundance of multiple intestinal bacteria. Although some genera were concomitantly decreased in both conditions, PsA samples had a lower abundance of reportedly beneficial taxa. This gut microbiota profile in PsA was similar to that previously described in patients with inflammatory bowel disease and was associated with changes in specific inflammatory proteins unique to this group, and distinct from that in patients with skin psoriasis and healthy controls. Thus, the role of the gut microbiome in the continuum of psoriasis-PsA pathogenesis and the associated immune response merits further study.

Because matrix metalloproteinases (MMPs) play roles in inflammatory tissue injury, we asked whether MMP secretion by gastric epithelial cells may contribute to gastric injury in response to signals involved in Helicobacter pylori-induced inflammation and/or cyclooxygenase inhibition. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and epidermal growth factor (EGF) stimulated gastric cell MMP-1 secretion, indicating that MMP-1 secretion occurs in inflammatory as well as non-inflammatory situations. MMP-1 secretion required activation of the MAPK Erk and subsequent protein synthesis but was down-regulated by the alternate MAPK, p38. In contrast, secretion of MMP-13 was stimulated by TNF-alpha/IL-1beta but not EGF and was Erk-independent and mediated by p38. MMP-13 secretion was more rapid (peak, 6 h) than MMP-1 (peakor =30 h) and only partly depended on protein synthesis, suggesting initial release of a pre-existing MMP-13 pool. Therefore, MMP-1 and MMP-13 secretion are differentially regulated by MAPKs. MMP-1 secretion was regulated by E prostaglandins (PGEs) in an Erk-dependent manner. PGEs enhanced Erk activation and MMP-1 secretion in response to EGF but inhibited Erk and MMP-1 when TNF-alpha and IL-1beta were the stimuli, indicating that the effects of PGEs on gastric cell responses are context-dependent. These data show that secretion of MMPs is differentially regulated by MAPKs and suggest mechanisms through which H. pylori infection and/or cyclooxygenase inhibition may induce epithelial cell signaling to contribute to gastric ulcerogenesis.

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis. About a quarter of patients with psoriasis of the skin will develop PsA, although it is currently challenging-if not impossible-to determine a priori which individuals will progress. Identification of biomarkers for screening, disease activity, joint damage, treatment response and comorbidities are therefore perceived as important clinical needs in the field. Over the last few years, several lines of investigation have advanced our knowledge of new markers for PsA and its outcomes, including genomic, proteomic, cellular and tissue studies. Imaging studies utilizing ultrasonography have been applied to better understand the natural history of the disease. Novel biomarkers, such as soluble proteins and microbiomics, are also being described. Although no biomarker has yet been validated for use in clinical practice, discovery studies are in progress and validation cohorts are being designed. In this report, we review the latest progress in biomarker research in PsA and its potential implications in pathogenesis, diagnosis and therapy.

RA is a complex multifactorial chronic disease that transitions through several stages. Multiple studies now support that there is a prolonged phase in early RA development during which there is serum elevation of RA-related autoantibodies including RF and ACPAs in the absence of clinically evident synovitis. This suggests that RA pathogenesis might originate in an extra-articular location, which we hypothesize is a mucosal site. In discussing this hypothesis, we will present herein the current understanding of mucosal immunology, including a discussion about the generation of autoimmune responses at these surfaces. We will also examine how other factors such as genes, microbes and other environmental toxins (including tobacco smoke) could influence the triggering of autoimmunity at mucosal sites and eventually systemic organ disease. We will also propose a research agenda to improve our understanding of the role of mucosal inflammation in the development of RA.

Rheumatoid arthritis (RA) is a prevalent systemic autoimmune disease, caused by a combination of genetic and environmental factors. Animal models suggest a role for intestinal bacteria in supporting the systemic immune response required for joint inflammation. Here we performed 16S sequencing on 114 stool samples from rheumatoid arthritis patients and controls, and shotgun sequencing on a subset of 44 such samples. We identified the presence of Prevotella copri as strongly correlated with disease in new-onset untreated rheumatoid arthritis (NORA) patients. Increases in Prevotella abundance correlated with a reduction in Bacteroides and a loss of reportedly beneficial microbes in NORA subjects. We also identified unique Prevotella genes that correlated with disease. Further, colonization of mice revealed the ability of P. copri to dominate the intestinal microbiota and resulted in an increased sensitivity to chemically induced colitis. This work identifies a potential role for P. copri in the pathogenesis of RA.

Therapeutic strategies for rheumatoid arthritis (RA) have evolved over time. Novel therapies have morphed in parallel to the ever-increasing understanding of RA pathogenesis, diagnosis and outcomes tools. For a century, the principal armamentarium was mainly composed by steroidal and non-steroidal anti-inflammatories. Over the last 25 years, however, the concept of disease-modifying anti-rheumatic drugs (DMARDs) has made possible the notion that the natural history of RA could actually be altered. Since then, synthetic DMARDs-particularly methotrexate (MTX) -have been used as monotherapy with significant success. This was followed by a revolutionary paradigm shift with the advent of anti-TNFα inhibitors and other "biologics" in the 1990s. Contemporary guidelines advocate for the use of a combina- tion therapy (i.e., MTX and a biologic) in aggressive RA cases given their proven additive effect. However, some patients are either intolerant to synthetic DMARDs or develop side effects that preclude their use. New data has recently emerged point- ing towards the potential for biologic monotherapy regimens in certain RA cases. This review will, therefore, describe the available evidence supporting the use of biologic DMARDs and the circumstances in which they are indicated.

B cells were originally considered key mediators in the pathogenesis of rheumatoid arthritis (RA). The presence of these cells in many RA synovial tissues and the discovery of rheumatoid factor had put B cells originally at the center of disease pathogenesis. That enthusiasm vanished shortly thereafter only to resurface in the last 15 years with the appearance of highly specific anti-cyclic citullinated protein antibodies. Rituximab, an anti-CD20 antibody that depletes mature B cells, was approved for the treatment of RA in 2006. Since then, B cell depletion strategies have proven efficacy for advanced disease, particularly in those patients that do not respond to DMARDs or TNFα inhibitors.

Background and objectives Airway abnormalities and increased lung tissue citrullination is found in both RA patients and individuals at at-risk for the development of disease. Recent data suggest that the gut (Prevotella copri) and oral (Porphyromonas gingivalis) microbiome might potentially contribute to the priming of an aberrant systemic immune response characteristic of RA. Our objective was to study whether the RA lung microbiome contains distinct taxonomic features associated with local and/or systemic autoimmunity. Materials and methods Bronchoalveolar lavage (BAL) samples from 20 subjects with RA, 10 with sarcoidosis (DC) and 24 healthy controls (HC) were obtained by research bronchoscopy. 16S rDNA sequencing was performed to define microbiota composition. Autoantibodies, including anti-CCP, RF and ACPAs were also measured in sera of RA subjects. Statistical analysis was performed using wilcoxon test and Spearman correlation. Results The16S sequencing data showed similar alpha/beta diversity between RA and DC groups, but significantly different from HC. Taxonomic comparison between groups was performed using LEfSe, which revealed several significant differences (LDA score>2). Multiple taxa, including Rhanella and Rhodanobacter were present only in the RA and DC groups, but completely absent from HC (p Conclusions Despite the relatively small number of samples analysed, several taxonomic differences were noted between groups. Correlations between relative abundance of specific taxa in RA BAL with serum autoantibodies (ie, anti-CCP) support an association between the lung microbiome and the host immune phenotype in RA. Further evaluation of functional aspects of this microbiome may provide further insights into its possible contribution to RA.

Objective To profile the abundance and diversity of subgingival oral microbiota in patients with never-treated, new-onset rheumatoid arthritis (RA). Methods Periodontal disease (PD) status, clinical activity, and sociodemographic factors were determined in patients with new-onset RA, patients with chronic RA, and healthy subjects. Multiplexed-454 pyrosequencing was used to compare the composition of subgingival microbiota and establish correlations between the presence/abundance of bacteria and disease phenotypes. Anti–Porphyromonas gingivalis antibody testing was performed to assess prior exposure to the bacterial pathogen P gingivalis. Results The more advanced forms of periodontitis were already present at disease onset in patients with new-onset RA. The subgingival microbiota observed in patients with new-onset RA was distinct from that found in healthy controls. In most cases, however, these microbial differences could be attributed to the severity of PD and were not inherent to RA. The presence and abundance of P gingivalis were also directly associated with the severity of PD and were not unique to RA. The presence of P gingivalis was not correlated with anti–citrullinated protein antibody (ACPA) titers. Overall exposure to P gingivalis was similar between patients with new-onset RA and controls, observed in 78% of patients and 83% of controls. The presence and abundance of Anaeroglobus geminatus correlated with the presence of ACPAs/rheumatoid factor. Prevotella and Leptotrichia species were the only characteristic taxa observed in patients with new-onset RA irrespective of PD status. Conclusion Patients with new-onset RA exhibited a high prevalence of PD at disease onset, despite their young age and paucity of smoking history. The subgingival microbiota profile in patients with new-onset RA was similar to that in patients with chronic RA and healthy subjects whose PD was of comparable severity. Although colonization with P gingivalis correlated with the severity of PD, overall exposure to P gingivalis was similar among the groups. The role of A geminatus and Prevotella/Leptotrichia species in this process merits further study.

Foxp3 + CD4 + CD25 high regulatory T cell (Treg) suppression of inflammation depends on T-cell receptor-mediated Nuclear Factor of Activated T cells c1 (NFATc1) activation with reduced Akt activity. We investigated the role of the scaffold protein Disc large homolog 1 (Dlgh1) in linking the T-cell receptor to this unique signaling outcome. The Treg immunological synapse (IS) recruited fourfold more Dlgh1 than conventional CD4 + T-cell IS. Tregs isolated from patients with active rheumatoid arthritis, or treated with tumor necrosis factor-α, displayed reduced function and diminished Dlgh1 recruitment to the IS. Furthermore, Dlgh1 silencing abrogated Treg function, impaired NFATc1 activation, reduced phosphatase and tensin homolog levels, and increased Akt activation. Dlgh1 operates independently of the negative feedback pathway mediated by the related adapter protein Carma1 and thus presents an array of unique targets to selectively manipulate Treg function.

Long regarded as proinflammatory molecules, prostaglandins (PGs) also have anti-inflammatory effects. Both prostaglandin D2 (PGD2) and its dehydration end product 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) seem to play important roles in regulating inflammation, via both receptor-dependent (DP1 and DP2 receptors) and receptor-independent mechanisms. Intracellular effects of PGD2 and 15d-PGJ2 that may suppress inflammation include inhibition of nuclear factor-κB (NF-κB) by multiple mechanisms (IκB kinase inhibition and blockade of NF-κB nuclear binding) and activation of peroxisome proliferator-activated receptor-γ (PPAR-γ). Prostaglandin F2α (PGF2α) may also have important anti-inflammatory effects, although current data are limited. In animal models, expression of both PGD and PGF synthases declines during acute inflammation, only to rise again during the resolution phase, suggesting their possible role in resolving inflammation. Prostaglandin E2 (PGE2), the classic model of a proinflammatory lipid mediator, also has anti-inflammatory effects that are both potent and context dependent. Thus, accumulating data suggest that PGs not only participate in initiation, but may also actively contribute to the resolution of inflammation. Indeed, classic inhibitors of PG synthesis such as nonselective and cyclooxygenase-2 (COX-2) selective inhibitors (nonsteroidal anti-inflammatory drugs) may actually prolong inflammation when administered during the resolution phase. These effects may regulate not only tissue inflammation but also vascular disease, possibly shedding light on the controversy surrounding nonsteroidal anti-inflammatory drug use and its relation to myocardial infarction. In this review, we summarize the current understanding of PGs as dichotomous molecules in the inflammatory process.

The production of nitric oxide (NO) by chondrocytes is increased in human osteoarthritis. The excessive production of NO inhibits matrix synthesis and promotes its degradation. Furthermore, by reacting with oxidants such as superoxide anion, NO promotes cellular injury and renders the chondrocyte susceptible to cytokine-induced apoptosis. Thus, NO produced by activated chondrocytes in diseased cartilage may modulate disease progression in osteoarthritis and should therefore be considered a potential target for therapeutic intervention.

Background Several clinically relevant and validated assessment tools are currently used in psoriatic arthritis (PsA), but most have limitations when applied in usual care situations (eg, requirements for formal joint counts and laboratory tests). Easy-to-use composite indices are needed to assess PsA at initial and follow-up visits in the clinical practice setting. Currently used in other chronic rheumatic conditions, RAPID3 is a simple composite index of 3 measures (ie, physical function, pain, and patient global assessment) that can be calculated in 5-10 seconds ( vs 114 seconds for DAS28) based on a patient self-report questionnaire completed in the waiting room. 1 Objectives To assess the performance of RAPID3 vs DAS28 and other commonly used instruments in patients with PsA. Methods Trial data from PRESTA 2 (baseline [BL] only) and PREPARE 3 (BL + wk 24) were analyzed. Correlations between RAPID3 and DAS28-CRP, CDAI, CPDAI, and DAPSA were analyzed using intraclass correlation coefficients (ICC; 95% CI). Treatment effect sizes were calculated for change from baseline to week 24 (PRESTA) and agreement in disease activity classifications compared at BL (PREPARE+PRESTA). Results A moderate degree of correlation was found between RAPID3 and other composite indices (table). In PRESTA, RAPID3 was most closely correlated with DAS28-CRP (ICC, 0.56, 0.67, and 0.51 at BL, wk 24, Δ at wk 24) and CPDAI (0.48, 0.65, 0.46). DAS28-CRP was the most sensitive tool in detecting treatment changes from BL to wk 24 in PRESTA (effect size, -1.75), and DAPSA the least sensitive (-0.94); RAPID3 showed moderate sensitivity (-1.33). Many patients who met criteria for high, moderate, low, and near-remission disease activity categories for RAPID3 satisfied criteria for similar categories for DAS28-ESR (38%, PREPARE; 51%, PRESTA) and CDAI (52%; 59%) at BL. Conclusions In clinical trials of PsA, the performance of RAPID3 proved to be satisfactory relative to other composite indices. Although additional research is needed, RAPID3 may provide a practical tool for use in the routine clinical care of this condition. References Pincus T, et al. Bull NYU Hosp Jt Dis. 2009;67:211-25. Sterry W, et al. BMJ. 2010;340:c147. Mease PJ, et al. J Am Acad Dermatol. 2013;69:729-35. Disclosure of Interest S. M. Reddy: None declared, J. U. Scher Grant/research support from: NIH, Arthritis Foundation, Consultant for: Janssen, Celgene, Novartis, Abbvie, A. Szumski Consultant for: Pfizer Inc, M.-A. Hsu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Marshall Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, H. Jones Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Y. Yazici Grant/research support from: BMS, Celgene, Genentech, Consultant for: BMS, Celgene, genentech, Employee of: Samumed

Humans and other mammals are not (and have never been) alone. From the moment we are born, millions of microorganisms populate our bodies and coexist with us rather peacefully for the rest of our lives. This massive anitgenic load derived from microorganisms (and their genomes) define the human microbiome. Micro-organisms living in or on us have evolved to extract the energy they require to survive, and in exchange they support the physiological, nutritional, metabolic and immune functions that have contributed to our evolutionary success. Although currently categorized as autoimmune disorders and regarded as complex genetic disease, the ultimate cause of rheumatoid arthritis (RA), psoriatic arthirits (PsA), and related conditions remain elusive. It seems that interplay between predisposing genetic factors and environmental triggers is required for disease manifestations. New insights from DNA sequence- based analyses of gut and skin microbial communities and a renewed interest in mucosal immunology suggest that the microbiome represents an important environmental factor that can modulate inflammation and autoimmune disease manifestations. Multiple animal models and novel human studies suggest a possible role for a disruption in the microbiome composition (dysbiosis) in the pathogenesis of inflammatory arthritis, presumably through activation of proinflammatory T-cells via antigenic molecules and/or bacterial-derived metabolites. Disclosure of Interest None declared

Background Rheumatoid arthritis (RA) is a complex, autoimmune disease in which several genetic and environmental factors play a role. Recent data suggest that the gut and oral microbiome might potentially contribute to an aberrant systemic immune response characteristic of RA. Among recently studied microbiota, both P. gingivalis in the oral cavity1 and P. copri2 in the gut have been implicated. Imaging abnormalities seen in RA patients and also in at-risk individuals for the development of disease3 along with the presence of autoantibodies in the airways4 implicates the lung as yet another site of autoimmunity generation in RA. Objectives To test whether the RA lung microbiome contains distinct taxonomic features that associate with local and/or systemic autoimmunity Methods Bronchoalveolar lavage (BAL) samples from 20 subjects with RA and 10 with sarcoidosis were obtained by research bronchoscopy. 16S rDNA sequencing was performed to define microbiota composition. Levels of arginine/citrulline were measured in BAL fluid using GC-MS for all samples. Autoantibodies, including anti-CCP, RF and ACPAs were also measured in RA subjects in BAL and serum. Statistical analysis was performed using wilcoxon test and Spearman correlation. Results There were no differences in demographic or clinical characteristics (including smoking status) between the groups. 16S sequencing data show similar alpha and beta diversity based on UniFrac between groups. Taxonomic comparison between RA and sarcoidosis was performed using LEfSe, which revealed several significant differences (LDA score>2). While RA BAL samples were enriched with Sphingobacteria, sarcoidosis BAL was enriched with Bacteroidia, Rhizobiales, Nitrospirales, and Campylobacter. GC-MS showed similar levels of arginine and citrulline in BAL for the sarcoidosis and RA groups. Raoultella and Barnesiella correlated with CCP2 levels in BAL (rho=0.49 and 0.47; p-value=0.026 and 0.032 respectively). Serum levels of CCP-IgA had a negative correlation with Massilia and Tannerella (rho= -0.63 and 0.53; p-value 0.003 and 0.016, respectively), and a positive correlation with Vagococcus and Lactobacillus (rho=0.59 and 0.54; p-value 0.006 and 0.014, respectively). Unclas_Lactobacillales also had a positive correlation with serum levels of RF-IgA (rho=0.71; p-value Conclusions Despite the relatively small number of samples analyzed, several taxonomic differences were noted between RA and Sarcoidosis. Correlations between relative abundance of specific taxa in BAL with serum autoantibodies (i.e., anti-CCP) support an association between the lung microbiome and the host immune phenotype in RA. Further evaluation of functional aspects of this microbiome may provide further insights into its possible contribution to RA. References Scher JU, Arthritis Rheum. 2012;64(10):3083-94. Scher JU, Elife. 2013 Nov 5;2:e01202. Willis VC, et al., Arthritis Rheum. 2013;65(10):2545-54. Reynisdottir G, et al., Arthritis Rheumatol. 2014;66(1):31-9 Disclosure of Interest None declared