C-terminal citrullinated peptide alters antigen-specific APC:T cell interactions leading to breach of immune tolerance.

In rheumatoid arthritis, the emergence of anti-citrullinated autoimmunity is associated with HLA-antigen-T cell receptor complexes. The precise mechanisms underpinning this breach of tolerance are not well understood. Porphyromonas gingivalis expresses an enzyme capable of non-endogenous C-terminal citrullination with potential to generate citrullinated autoantigens. Here we document how C-terminal citrullination of ovalbumin peptide323-339 alters the interaction between antigen-presenting cells and OTII T cells to induce functional changes in responding T cells. These data reveal that C-terminal citrullination is sufficient to breach T cell peripheral tolerance in vivo and reveal the potential of C-terminal citrullination to lower the threshold for T cell activation. Finally, we demonstrate a role for the IL-2/STAT5/CD25 signalling axis in breach of tolerance. Together, our data identify a tractable mechanism and targetable pathways underpinning breach of tolerance in rheumatoid arthritis and provide new conceptual insight into the origins of anti-citrullinated autoimmunity.

Stratification of alopecia areata reveals involvement of CD4 T cell populations and altered faecal microbiota.

Alopecia areata (AA) is an immune-mediated disease that causes non-scarring hair loss. Autoreactive CD8 T cells are key pathogenic effectors in the skin, and AA has been associated both with atopy and with perturbations in intestinal homeostasis. This study aimed to investigate mechanisms driving AA by characterizing the circulating immunophenotype and faecal microbiome, and by stratifying AA to understand how identified signatures associated with heterogeneous clinical features of the condition. Flow cytometric analyses identified alterations in circulating B cells and CD4 T cells, while 16S sequencing identified changes in alpha and beta diversity in the faecal microbiome in AA. The proportions of transitional and naïve B cells were found to be elevated in AA, particularly in AA samples from individuals with >50% hair loss and those with comorbid atopy, which is commonly associated with extensive hair loss. Although significant changes in circulating CD8 T cells were not observed, we found significant changes in CD4+ populations. In individuals with <50% hair loss higher frequencies of CCR6+CD4 ("Th17") and CCR6+CXCR3+CD4 ("Th1/17") T cells were found. While microbial species richness was not altered, AA was associated with reduced evenness and Shannon diversity of the intestinal microbiota, again particularly in those with <50% hair loss. We have identified novel immunological and microbial signatures in individuals with alopecia areata. Surprisingly, these are associated with lower levels of hair loss, and may therefore provide a rationale for improved targeting of molecular therapeutics.

TRAFIC: statistical design and analysis plan for a pragmatic early phase 1/2 Bayesian adaptive dose escalation trial in rheumatoid arthritis.

BACKGROUND: Adaptive model-based dose-finding designs have demonstrated advantages over traditional rule-based designs but have increased statistical complexity but uptake has been slow especially outside of cancer trials. TRAFIC is a multi-centre, early phase trial in rheumatoid arthritis incorporating a model-based design. METHODS: A Bayesian adaptive dose-finding phase I trial rolling into a single-arm, single-stage phase II trial. Model parameters for phase I were chosen via Monte Carlo simulation evaluating objective performance measures under clinically relevant scenarios and incorporated stopping rules for early termination. Potential designs were further calibrated utilising dose transition pathways. DISCUSSION: TRAFIC is an MRC-funded trial of a re-purposed treatment demonstrating that it is possible to design, fund and implement a model-based phase I trial in a non-cancer population within conventional research funding tracks and regulatory constraints. The phase I design allows borrowing of information from previous trials, all accumulated data to be utilised in decision-making, verification of operating characteristics through simulation, improved understanding for management and oversight teams through dose transition pathways. The rolling phase II design brings efficiencies in trial conduct including site and monitoring activities and cost. TRAFIC is the first funded model-based dose-finding trial in inflammatory disease demonstrating that small phase I/II trials can have an underlying statistical basis for decision-making and interpretation. TRIAL REGISTRATION: Trials Registration: ISRCTN, ISRCTN36667085 . Registered on September 26, 2014.

Efficacy of secukinumab and adalimumab in patients with psoriatic arthritis and concomitant moderate-to-severe plaque psoriasis: results from EXCEED, a randomized, double-blind head-to-head monotherapy study.

BACKGROUND: Secukinumab [an interleukin (IL)-17A inhibitor] has demonstrated significantly higher efficacy vs. etanercept (a tumour necrosis factor inhibitor) and ustekinumab (an IL-12/23 inhibitor) in patients with moderate-to-severe plaque psoriasis. OBJECTIVES: To report 52-week results from a prespecified analysis of patients with active psoriatic arthritis (PsA) having concomitant moderate-to-severe plaque psoriasis from the head-to-head EXCEED monotherapy study comparing secukinumab with adalimumab. METHODS: Patients were randomized to receive secukinumab 300 mg via subcutaneous injection at baseline, week 1-4, and then every 4 weeks until week 48 or adalimumab 40 mg via subcutaneous injection every 2 weeks from baseline until week 50. Assessments in patients with concomitant moderate-to-severe psoriasis, defined as having affected body surface area > 10% or Psoriasis Area and Severity Index (PASI) ≥ 10 at baseline, included musculoskeletal, skin and quality-of-life outcomes. Missing data were handled using multiple imputation. RESULTS: Of the 853 patients [secukinumab (N = 426), adalimumab (N = 427)], 211 (24·7%) had concomitant moderate-to-severe psoriasis [secukinumab (N = 110, 25·8%), adalimumab (N = 101, 23·7%)]. Up to week 50, 5·5% of patients discontinued secukinumab vs.17·8% in the adalimumab group. The proportion of patients who achieved American College of Rheumatology (ACR) 20 response was 76·4% with secukinumab vs. 68·3% with adalimumab (P = 0·175), PASI 100 response was 39·1% vs. 23·8% (P = 0·013), and simultaneous improvement in ACR 50 and PASI 100 response at week 52 was 28·2% vs. 17·7%, respectively (P = 0·06). Secukinumab demonstrated consistently higher responses vs. adalimumab across skin endpoints. CONCLUSIONS: This prespecified analysis in PsA patients with concomitant moderate-to-severe plaque psoriasis in the EXCEED study provides further evidence that IL-17 inhibitors offer a comprehensive biological treatment to manage the concomitant features of psoriasis and PsA.

Risk-mitigating behaviours in people with inflammatory skin and joint disease during the COVID-19 pandemic differ by treatment type: a cross-sectional patient survey.

BACKGROUND: Registry data suggest that people with immune-mediated inflammatory diseases (IMIDs) receiving targeted systemic therapies have fewer adverse coronavirus disease 2019 (COVID-19) outcomes compared with patients receiving no systemic treatments. OBJECTIVES: We used international patient survey data to explore the hypothesis that greater risk-mitigating behaviour in those receiving targeted therapies may account, at least in part, for this observation. METHODS: Online surveys were completed by individuals with psoriasis (globally) or rheumatic and musculoskeletal diseases (RMDs) (UK only) between 4 May and 7 September 2020. We used multiple logistic regression to assess the association between treatment type and risk-mitigating behaviour, adjusting for clinical and demographic characteristics. We characterized international variation in a mixed-effects model. RESULTS: Of 3720 participants (2869 psoriasis, 851 RMDs) from 74 countries, 2262 (60·8%) reported the most stringent risk-mitigating behaviour (classified here under the umbrella term 'shielding'). A greater proportion of those receiving targeted therapies (biologics and Janus Kinase inhibitors) reported shielding compared with those receiving no systemic therapy [adjusted odds ratio (OR) 1·63, 95% confidence interval (CI) 1·35-1·97]. The association between targeted therapy and shielding was preserved when standard systemic therapy was used as the reference group (OR 1·39, 95% CI 1·23-1·56). Shielding was associated with established risk factors for severe COVID-19 [male sex (OR 1·14, 95% CI 1·05-1·24), obesity (OR 1·37, 95% CI 1·23-1·54), comorbidity burden (OR 1·43, 95% CI 1·15-1·78)], a primary indication of RMDs (OR 1·37, 95% CI 1·27-1·48) and a positive anxiety or depression screen (OR 1·57, 95% CI 1·36-1·80). Modest differences in the proportion shielding were observed across nations. CONCLUSIONS: Greater risk-mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID-19 outcomes. The behaviour variation across treatment groups, IMIDs and nations reinforces the need for clear evidence-based patient communication on risk-mitigation strategies and may help inform updated public health guidelines as the pandemic continues.

Immunoglobulin A antibodies to oxidized collagen type II as a potential biomarker for the stratification of spondyloarthritis from rheumatoid arthritis.

OBJECTIVES: The discovery of diseased tissue-specific neoantigens offers the opportunity to develop important disease tissue-specific biomarkers that can help in the prediction, diagnosis, and stratification of diseases. This opportunity is specifically significant for autoimmune diseases where diagnostic biomarkers are not available. Inflammatory autoimmune diseases are commonly associated with local generation of large amounts of reactive oxidants. We have previously identified oxidative post-translationally modified (oxPTM) tissue-specific neoantigens in rheumatoid arthritis (RA) and type 1 diabetes that elicit an immune response. In the current study, we studied the presence and clinical significance of antibodies to oxPTM collagen type II (CII) in patients with spondyloarthritis (SpA). METHOD: Levels of antibodies specific to native CII and oxPTM-CII were assessed by enzyme-linked immunosorbent assay. RESULTS: Immunoglobulin G (IgG) binding to oxPTM-CII was observed in 52%, 83%, and 28% of serum samples from patients with axial spondyloarthritis (axSpA), RA, and psoriatic arthritis (PsA), respectively. Importantly, while strong IgA anti-oxPTM-CII responses were detected in axSpA and PsA patients, with 47% and 84% respective binders, no IgA anti-oxPTM-CII was detected in RA patients. IgA anti-oxPTM-CII reactivity in axSpA patients treated with biologics was higher and more frequent, with 85% binders compared to 9% binders in patients treated with synthetic disease-modifying anti-rheumatic drugs. CONCLUSION: Our data imply that SpA and PsA are associated with the presence of antibodies to oxPTM-CII, suggesting that there may be a humoral component that may distinguish patients with SpA from RA. Our approach could be adapted to other diseases, particularly to inflammatory autoimmune diseases.

Differential CpG DNA methylation in peripheral naïve CD4+ T-cells in early rheumatoid arthritis patients.

BACKGROUND: The genetic risk associated with rheumatoid arthritis (RA) includes genes regulating DNA methylation, one of the hallmarks of epigenetic re-programing, as well as many T-cell genes, with a strong MHC association, pointing to immunogenetic mechanisms as disease triggers leading to chronicity. The aim of our study was to explore DNA methylation in early, drug-naïve RA patients, towards a better understanding of early events in pathogenesis. RESULT: Monocytes, naïve and memory CD4+ T-cells were sorted from 6 healthy controls and 10 RA patients. DNA methylation was assessed using a genome-wide Illumina 450K CpG promoter array. Differential methylation was confirmed using bisulfite sequencing for a specific gene promoter, ELISA for several cytokines and flow cytometry for cell surface markers. Differentially methylated (DM) CpGs were observed in 1047 genes in naïve CD4+ T-cells, 913 in memory cells and was minimal in monocytes with only 177 genes. Naive CD4+ T-cells were further investigated as presenting differential methylation in the promoter of > 500 genes associated with several disease-relevant pathways, including many cytokines and their receptors. We confirmed hypomethylation of a region of the TNF-alpha gene in early RA and differential expression of 3 cytokines (IL21, IL34 and RANKL). Using a bioinformatics package (DMRcate) and an in-house analysis based on differences in ß values, we established lists of DM genes between health and RA. Publicly available gene expression data were interrogated to confirm differential expression of over 70 DM genes. The lists of DM genes were further investigated based on a functional relationship database analysis, which pointed to an IL6/JAK1/STAT3 node, related to TNF-signalling and engagement in Th17 cell differentiation amongst many pathways. Five DM genes for cell surface markers (CD4, IL6R, IL2RA/CD25, CD62L, CXCR4) were investigated towards identifying subpopulations of CD4+ T-cells undergoing these modifications and pointed to a subset of naïve T-cells, with high levels of CD4, IL2R, and CXCR4, but reduction and loss of IL6R and CD62L, respectively. CONCLUSION: Our data provided novel conceptual advances in the understanding of early RA pathogenesis, with implications for early treatment and prevention.

Reflections on 'older' drugs: learning new lessons in rheumatology.

The management of rheumatic and musculoskeletal diseases has transformed over two decades of exciting discoveries regarding pathogenesis and innovative drug development. The introduction of sophisticated immunomodulatory therapies has given renewed hope to many patients, but notable challenges remain within the field of rheumatology. Before the advent of biologic therapies, conventional synthetic DMARDs (csDMARDs) provided effective disease control for some patients, although a comprehensive understanding of the mechanisms by which these drugs exert their effects remained elusive. Reflecting upon the efficacy and mechanisms of action of csDMARDs can provide intriguing insights. First, contemplating past approaches brings our remarkable current approaches concerning pathogenesis-driven discovery and drug development into sharper focus. Second, increased understanding of the mode of action of these older drugs might in turn provide exciting opportunities for the understanding of disease and for the development of future therapies.

Alopecia areata is characterized by dysregulation in systemic type 17 and type 2 cytokines, which may contribute to disease-associated psychological morbidity.

BACKGROUND: Alopecia areata (AA) is a common autoimmune disease, causing patchy hair loss that can progress to involve the entire scalp (totalis) or body (universalis). CD8+ NKG2D+ T cells dominate hair follicle pathogenesis, but the specific mechanisms driving hair loss are not fully understood. OBJECTIVES: To provide a detailed insight into the systemic cytokine signature associated with AA, and to assess the association between cytokines and depression. METHODS: We conducted multiplex analysis of plasma cytokines from patients with AA, patients with psoriatic arthritis (PsA) and healthy controls. We used the Hospital Anxiety and Depression Scale (HADS) to assess the occurrence of depression and anxiety in our cohort. RESULTS: Our analysis identified a systemic inflammatory signature associated with AA, characterized by elevated levels of interleukin (IL)-17A, IL-17F, IL-21 and IL-23 indicative of a type 17 immune response. Circulating levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25) were also significantly increased in AA. In comparison with PsA, AA was associated with higher levels of IL-17F, IL-17E and IL-23. We hypothesized that circulating inflammatory cytokines may contribute to wider comorbidities associated with AA. Our assessment of psychiatric comorbidity in AA using HADS scores showed that 18% and 51% of people with AA experienced symptoms of depression and anxiety, respectively. Using linear regression modelling, we identified that levels of IL-22 and IL-17E are positively and significantly associated with depression. CONCLUSIONS: Our data highlight changes in both type 17 and type 2 cytokines among people with AA, suggesting that complex systemic cytokine profiles may contribute both to the pathogenesis of AA and to the associated depression. What's already known about this topic? NKG2D+ CD8+ T cells cause hair loss in alopecia areata (AA) but the immunological mechanisms underlying the disease are not fully understood. AA is associated with changes in levels of interleukin (IL)-6, tumour necrosis factor-α, IL-1ß and type 17 cytokines. Psychiatric comorbidity is common among people with AA. What does this study add? People with AA have increased plasma levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25), in addition to the type 17 cytokines IL-17A, IL-21, IL-23 and IL-17F. Levels of IL-17E and IL-22 positively predict depression score. What is the translational message? AA is associated with increased levels of multiple inflammatory cytokines, implicating both type 17- and type 2 immune pathways. Our data indicate that therapeutic strategies for treating AA may need to address the underlying type 17- and type 2 immune dysregulation, rather than focusing narrowly on the CD8+ T-cell response. An immunological mechanism might contribute directly to the depression observed in people with AA.

Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data.

BACKGROUND: Secukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits interleukin (IL)-17A, has been shown to have robust efficacy in the treatment of moderate-to-severe psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) demonstrating a rapid onset of action and sustained long-term clinical responses with a consistently favorable safety profile in multiple Phase 2 and 3 trials. Here, we report longer-term pooled safety and tolerability data for secukinumab across three indications (up to 5 years of treatment in PsO and PsA; up to 4 years in AS). METHODS: The integrated clinical trial safety dataset included data pooled from 21 randomized controlled clinical trials of secukinumab 300 or 150 or 75 mg in PsO (14 Phase 3 trials and 1 Phase 4 trial), PsA (3 Phase 3 trials), and AS (3 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of June 25, 2017. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 patient-years. Analyses included all patients who received ≥ 1 dose of secukinumab. RESULTS: A total of 5181, 1380, and 794 patients from PsO, PsA, and AS clinical trials representing secukinumab exposures of 10,416.9, 3866.9, and 1943.1 patient-years, respectively, and post-marketing data from patients with a cumulative exposure to secukinumab of ~ 96,054 patient-years were included in the analysis. The most frequent AE was upper respiratory tract infection. EAIRs across PsO, PsA, and AS indications were generally low for serious infections (1.4, 1.9, and 1.2, respectively), Candida infections (2.2, 1.5, and 0.7, respectively), inflammatory bowel disease (0.01, 0.05, and 0.1, respectively), and major adverse cardiac events (0.3, 0.4, and 0.6, respectively). No cases of tuberculosis reactivation were reported. The incidence of treatment-emergent anti-drug antibodies was low with secukinumab across all studies, with no discernible loss of efficacy, unexpected alterations in pharmacokinetics, or association with immunogenicity-related AEs. CONCLUSIONS: Secukinumab demonstrated a favorable safety profile over long-term treatment in patients with PsO, PsA, and AS. This comprehensive assessment demonstrated that the safety profile of secukinumab was consistent with previous reports in patients with PsO, PsA, and AS, supporting its long-term use in these chronic conditions.

Tranexamic acid toxicity in human periarticular tissues.

OBJECTIVES: Tranexamic acid (TXA) is an anti-fibrinolytic medication commonly used to reduce perioperative bleeding. Increasingly, topical administration as an intra-articular injection or perioperative wash is being administered during surgery. Adult soft tissues have a poor regenerative capacity and therefore damage to these tissues can be harmful to the patient. This study investigated the effects of TXA on human periarticular tissues and primary cell cultures using clinically relevant concentrations. METHODS: Tendon, synovium, and cartilage obtained from routine orthopaedic surgeries were used for ex vivo and in vitro studies using various concentrations of TXA. The in vitro effect of TXA on primary cultured tenocytes, fibroblast-like synoviocytes, and chondrocytes was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assays, fluorescent microscopy, and multi-protein apoptotic arrays for cell death. RESULTS: There was a significant (p < 0.01) increase in cell death within all tissue explants treated with 100 mg/ml TXA. MTT assays revealed a significant (p < 0.05) decrease in cell viability in all tissues following treatment with 50 mg/ml or 100 mg/ml of TXA within four hours. There was a significant (p < 0.05) increase in cell apoptosis after one hour of exposure to TXA (100 mg/ml) in all tissues. CONCLUSION: The current study demonstrates that TXA caused significant periarticular tissue toxicity ex vivo and in vitro at commonly used clinical concentrations.Cite this article: M. McLean, K. McCall, I. D. M. Smith, M. Blyth, S. M. Kitson, L. A. N. Crowe, W. J. Leach, B. P. Rooney, S. J. Spencer, M. Mullen, J. L. Campton, I. B. McInnes, M. Akbar, N. L. Millar. Tranexamic acid toxicity in human periarticular tissues. Bone Joint Res 2019;8:11-18. DOI: 10.1302/2046-3758.81.BJR-2018-0181.R1.

JAK Inhibitors in Rheumatology: Implications for Paediatric Syndromes?

PURPOSE OF REVIEW: Given the recent increase in the profile and use of Janus kinase inhibitors (JAKinibs) in adult patients with rheumatic diseases, we aimed to review the current evidence accruing for use in paediatric rheumatology patients. RECENT FINDINGS: Significant advances have been made in the management of rheumatic diseases in the past two decades. The introduction of biologic agents in both adults and children has provided significant improvements to patient outcomes and led to better quality of life. Moreover, responses to similar agents allude to common effector pathways operating across juvenile and adult synovitis especially. However, inefficacy and intolerance of these agents leads to a subset of children with limited treatment options. Since 2012, Janus kinase (JAK) inhibitors (JAKinibs), a novel group of oral small molecule inhibitors, have demonstrated their efficacy in several forms of adult inflammatory arthritis, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA). There are hopes that these successes will be transferable to the paediatric population. In the following review, we discuss the development and progress of JAKinibs in this regard.

Driving chronicity in rheumatoid arthritis: perpetuating role of myeloid cells.

Acute inflammation is a complex and tightly regulated homeostatic process that includes leucocyte migration from the vasculature into tissues to eliminate the pathogen/injury, followed by a pro-resolving response promoting tissue repair. However, if inflammation is uncontrolled as in chronic diseases such as rheumatoid arthritis (RA), it leads to tissue damage and disability. Synovial tissue inflammation in RA patients is maintained by sustained activation of multiple inflammatory positive-feedback regulatory pathways in a variety of cells, including myeloid cells. In this review, we will highlight recent evidence uncovering biological mechanisms contributing to the aberrant activation of myeloid cells that contributes to perpetuation of inflammation in RA, and discuss emerging data on anti-inflammatory mediators contributing to sustained remission that may inform a novel category of therapeutic targets.

Decreased hippocampal translocator protein (18 kDa) expression in alcohol dependence: a [11C]PBR28 PET study.

Repeated withdrawal from alcohol is clinically associated with progressive cognitive impairment. Microglial activation occurring during pre-clinical models of alcohol withdrawal is associated with learning deficits. We investigated whether there was microglial activation in recently detoxified alcohol-dependent patients (ADP), using [11C]PBR28 positron emission tomography (PET), selective for the 18kDa translocator protein (TSPO) highly expressed in activated microglia and astrocytes. We investigated the relationship between microglial activation and cognitive performance. Twenty healthy control (HC) subjects (45±13; M:F 14:6) and nine ADP (45±6, M:F 9:0) were evaluated. Dynamic PET data were acquired for 90 min following an injection of 331±15 MBq [11C]PBR28. Regional volumes of distribution (VT) for regions of interest (ROIs) identified a priori were estimated using a two-tissue compartmental model with metabolite-corrected arterial plasma input function. ADP had an ~20% lower [11C]PBR28 VT, in the hippocampus (F(1,24) 5.694; P=0.025), but no difference in VT in other ROIs. Hippocampal [11C]PBR28 VT was positively correlated with verbal memory performance in a combined group of HC and ADP (r=0.720, P<0.001), an effect seen in HC alone (r=0.738; P=0.001) but not in ADP. We did not find evidence for increased microglial activation in ADP, as seen pre-clinically. Instead, our findings suggest lower glial density or an altered activation state with lower TSPO expression. The correlation between verbal memory and [11C]PBR28 VT, raises the possibility that abnormalities of glial function may contribute to cognitive impairment in ADP.

EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update.

Patients with rheumatoid arthritis (RA) and other inflammatory joint disorders (IJD) have increased cardiovascular disease (CVD) risk compared with the general population. In 2009, the European League Against Rheumatism (EULAR) taskforce recommended screening, identification of CVD risk factors and CVD risk management largely based on expert opinion. In view of substantial new evidence, an update was conducted with the aim of producing CVD risk management recommendations for patients with IJD that now incorporates an increasing evidence base. A multidisciplinary steering committee (representing 13 European countries) comprised 26 members including patient representatives, rheumatologists, cardiologists, internists, epidemiologists, a health professional and fellows. Systematic literature searches were performed and evidence was categorised according to standard guidelines. The evidence was discussed and summarised by the experts in the course of a consensus finding and voting process. Three overarching principles were defined. First, there is a higher risk for CVD in patients with RA, and this may also apply to ankylosing spondylitis and psoriatic arthritis. Second, the rheumatologist is responsible for CVD risk management in patients with IJD. Third, the use of non-steroidal anti-inflammatory drugs and corticosteroids should be in accordance with treatment-specific recommendations from EULAR and Assessment of Spondyloarthritis International Society. Ten recommendations were defined, of which one is new and six were changed compared with the 2009 recommendations. Each designated an appropriate evidence support level. The present update extends on the evidence that CVD risk in the whole spectrum of IJD is increased. This underscores the need for CVD risk management in these patients. These recommendations are defined to provide assistance in CVD risk management in IJD, based on expert opinion and scientific evidence.

Mast Cells Contribute to Porphyromonas gingivalis-induced Bone Loss.

Periodontitis is a chronic inflammatory and bone-destructive disease. Development of periodontitis is associated with dysbiosis of the microbial community, which may be caused by periodontal bacteria, such as Porphyromonas gingivalis Mast cells are sentinels at mucosal surfaces and are a potent source of inflammatory mediators, including tumor necrosis factors (TNF), although their role in the pathogenesis of periodontitis remains to be elucidated. This study sought to determine the contribution of mast cells to local bone destruction following oral infection with P. gingivalis Mast cell-deficient mice (Kit(W-sh/W-sh)) were protected from P. gingivalis-induced alveolar bone loss, with a reduction in anti-P. gingivalis serum antibody titers compared with wild-type infected controls. Furthermore, mast cell-deficient mice had reduced expression of Tnf, Il6, and Il1b mRNA in gingival tissues compared with wild-type mice. Mast cell-engrafted Kit(W-sh/W-sh) mice infected with P. gingivalis demonstrated alveolar bone loss and serum anti-P. gingivalis antibody titers equivalent to wild-type infected mice. The expression of Tnf mRNA in gingival tissues of Kit(W-sh/W-sh) mice was elevated following the engraftment of mast cells, indicating that mast cells contributed to the Tnf transcript in gingival tissues. In vitro, mast cells degranulated and released significant TNF in response to oral bacteria, and neutralizing TNF in vivo abrogated alveolar bone loss following P. gingivalis infection. These data indicate that mast cells and TNF contribute to the immunopathogenesis of periodontitis and may offer therapeutic targets.

European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update.

BACKGROUND: Since the publication of the European League Against Rheumatism recommendations for the pharmacological treatment of psoriatic arthritis (PsA) in 2012, new evidence and new therapeutic agents have emerged. The objective was to update these recommendations. METHODS: A systematic literature review was performed regarding pharmacological treatment in PsA. Subsequently, recommendations were formulated based on the evidence and the expert opinion of the 34 Task Force members. Levels of evidence and strengths of recommendations were allocated. RESULTS: The updated recommendations comprise 5 overarching principles and 10 recommendations, covering pharmacological therapies for PsA from non-steroidal anti-inflammatory drugs (NSAIDs), to conventional synthetic (csDMARD) and biological (bDMARD) disease-modifying antirheumatic drugs, whatever their mode of action, taking articular and extra-articular manifestations of PsA into account, but focusing on musculoskeletal involvement. The overarching principles address the need for shared decision-making and treatment objectives. The recommendations address csDMARDs as an initial therapy after failure of NSAIDs and local therapy for active disease, followed, if necessary, by a bDMARD or a targeted synthetic DMARD (tsDMARD). The first bDMARD would usually be a tumour necrosis factor (TNF) inhibitor. bDMARDs targeting interleukin (IL)12/23 (ustekinumab) or IL-17 pathways (secukinumab) may be used in patients for whom TNF inhibitors are inappropriate and a tsDMARD such as a phosphodiesterase 4-inhibitor (apremilast) if bDMARDs are inappropriate. If the first bDMARD strategy fails, any other bDMARD or tsDMARD may be used. CONCLUSIONS: These recommendations provide stakeholders with an updated consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes in PsA, based on a combination of evidence and expert opinion.

Periodontitis in the absence of B cells and specific anti-bacterial antibody.

Periodontitis (PD) results from complex interactions between a dysbiotic oral microbiota and a dysregulated host immune response. The inflammatory infiltrate in the gingiva of PD patients includes an abundance of B cells, implicating these cells in the immunopathology. We sought to investigate the role of B cells in PD using a murine model. Wild-type or B-cell-deficient (µMT) mice were orally infected with Porphyromonas gingivalis. One or six weeks following infection, lymphocyte populations in the gingiva and cervical draining lymph nodes (dLN) were analysed by flow cytometry; serum anti-P. gingivalis IgG antibody titers were measured by enzyme-linked immunosorbent assay, and alveolar bone loss was determined. In wild-type mice, the percentage of gingival B cells expressing receptor activator of nuclear factor-κB ligand (RANKL) was significantly increased 1 week post-infection (5.36% control versus 11% PD, P < 0.01). The percentage of Fas(+) GL7(+) germinal centre B cells in the dLN was significantly increased at both 1 week (2.03% control versus 6.90% PD, P < 0.01) and 6 weeks (4.45% control versus 8.77% PD, P < 0.05) post-infection. B-cell-deficient mice were protected from P. gingivalis-induced alveolar bone loss, with a lack of B-cell proliferation and lack of CD4(+) CD44(+) CD62L(-) T-cell generation in the dLN, and absence of serum anti-P. gingivalis antibodies. Our data imply a pathological role for B cells in PD, and that selective targeting of this immune axis may have a role in treating severe periodontal disease.

Ultrasound-guided synovial biopsy: a safe, well-tolerated and reliable technique for obtaining high-quality synovial tissue from both large and small joints in early arthritis patients.

OBJECTIVE: To determine the tolerability, safety and yield of synovial tissue in an early arthritis cohort using a minimally invasive, ultrasound (US)-guided, synovial biopsy technique in small, medium and large joints. METHODS: 93 sequential biopsy procedures were assessed from a total of 57 patients (baseline and 36 repeat biopsies at 6 months) recruited as part of the 'Pathobiology of Early Arthritis Cohort' study. Patients completed a tolerability questionnaire prior to and following the synovial biopsy procedure. The synovial biopsy was performed under US guidance with US images of the joint recorded prior to each procedure. Synovial tissue was harvested for immunohistochemistry and RNA extraction. RESULTS: Five different joint sites were biopsied (knee, elbow, wrist, metacarpal phalangeal and proximal interphalangeal). No significant complications were reported following the procedure. No difference in pain, swelling and stiffness of the biopsied joint from before and after the procedure was demonstrated. A median of 14 biopsy samples was retrieved from each procedure with 93% of biopsy procedures yielding good quality tissue. RNA yield was good in all joints and in repeat biopsies. Multivariant analysis demonstrated a significantly greater yield of RNA and graded tissue in relation to a high prebiopsy, grey-scale synovitis score (0-3, semiquantitative). CONCLUSIONS: A minimally invasive approach to synovial tissue harvesting, using US guidance, is both safe and well-tolerated by patients. Tissue quality/RNA yield is preserved in subsequent biopsies following therapeutic intervention. A high US grey-scale synovitis score is a predictor of good quality/quantity of tissue and RNA.

Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases.

Protein kinases mediate protein phosphorylation, which is a fundamental component of cell signalling, with crucial roles in most signal transduction cascades: from controlling cell growth and proliferation to the initiation and regulation of immunological responses. Aberrant kinase activity is implicated in an increasing number of diseases, with more than 400 human diseases now linked either directly or indirectly to protein kinases. Protein kinases are therefore regarded as highly important drug targets, and are the subject of intensive research activity. The success of small molecule kinase inhibitors in the treatment of cancer, coupled with a greater understanding of inflammatory signalling cascades, has led to kinase inhibitors taking centre stage in the pursuit for new anti-inflammatory agents for the treatment of immune-mediated diseases. Herein we discuss the main classes of kinase inhibitors; namely Janus kinase (JAK), mitogen-activated protein kinase (MAPK) and spleen tyrosine kinase (Syk) inhibitors. We provide a mechanistic insight into how these inhibitors interfere with kinase signalling pathways and discuss the clinical successes and failures in the implementation of kinase-directed therapeutics in the context of inflammatory and autoimmune disorders.