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Objective To investigate the association between clinical joint tenderness and intra- and periarticular inflammation as assessed by ultrasound and MRI in patients with active PsA and to explore if the associations differ according to patient-reported outcomes (PROs) and structural damage. Methods Forty-one patients with active PsA and hand involvement had 76/78 joints examined for swelling/tenderness and ultrasound and MRI of 24 and 12 finger joints, respectively. Synovitis, tenosynovitis, periarticular inflammation and erosions were assessed using OMERACT definitions and scoring systems. Correlation between imaging inflammation sum-scores (intra-and periarticular) and tender/swollen joint counts were calculated using Spearman’s rho, agreement at joint level was examined using prevalence and bias adjusted kappa (PABAK). Subgroup analyses explored the influence of PROs and radiographic erosive disease on these associations. Results No significant correlations were found between tender or swollen joint counts and imaging inflammation sum-scores (rho = −0.31–0.38). In patients with higher level of overall pain, disability and lower self-reported mental health, a tendency towards negative correlations were found. At joint level, intra- and periarticular imaging inflammatory lesions had slight agreement with joint tenderness (PABAK = 0.02–0.19) and slight to moderate with swelling (PABAK = 0.16–0.54). For tender joints, agreement with imaging inflammation was even weaker in patients with either high overall pain scores, high disability scores, and/or non-erosive disease. Conclusion Joint tenderness had low association with imaging signs of inflammation in PsA patients, particularly in patients with high self-reported pain, disability and low mental health, indicating that tenderness is influenced by other parameters than local inflammation.

Objectives: This case control study examined the associations of HLA antigens and periodontitis with the salivary level of active MMP-8 (aMMP-8). Materials and Methods: A total of 202 subjects, registered as Swiss bone marrow donors, participated in the study. HLA-A, -B, and -C types were determined by serology or PCR. Saliva samples were collected from subjects, followed by a periodontal examination. The salivary level of aMMP-8 was determined with immunofluorometric assay. Results: The mean salivary level of aMMP-8 was directly comparable to the grade of periodontitis and increased from healthy to mild/moderate to severe (125.0 +/- 132.1, 200.6 +/- 170.2, 290.1 +/- 202.3 ng/ml; p < 0.001 between each group, respectively). The only association between the HLA types and the salivary level of aMMP-8 was observed in subjects with HLA-A11. Subjects with healthy periodontium and HLA-A11 had a lower level of aMMP-8 (49.2 +/- 32.5 ng/ml) compared with subjects without HLA-A11 (123.6 +/- 119.2; p = 0.048). Among subjects with periodontitis, a higher level of aMMP-8 (394.2 +/- 255.6 ng/ml) was observed in subjects with HLA-A11 compared with subjects without HLA-A11 (201.1 +/- 146.1 ng/ml; p < 0.002). This finding was statistically significant also after adjusting for sex, age, smoking, tooth brushing and the number of medications (p < 0.05). Conclusions: HLA-A11 is associated with the salivary level of aMMP-8 which contributes to the subject's immune and inflammatory response in periodontium.

Objectives Survival extrapolation of trial outcomes is required for health economic evaluation. Generally, all-cause mortality (ACM) is modeled using standard parametric distributions, often without distinguishing disease-specific/excess mortality and general population background mortality (GPM). Recent National Institute for Health and Care Excellence guidance (Technical Support Document 21) recommends adding GPM hazards to disease-specific/excess mortality hazards in the log-likelihood function (“internal additive hazards”). This article compares alternative extrapolation approaches with and without GPM adjustment. Methods Survival extrapolations using the internal additive hazards approach (1) are compared to no GPM adjustment (2), applying GPM hazards once ACM hazards drop below GPM hazards (3), adding GPM hazards to ACM hazards (4), and proportional hazards for ACM versus GPM hazards (5). The fit, face validity, mean predicted life-years, and corresponding uncertainty measures are assessed for the active versus control arms of immature and mature (30- and 75-month follow-up) multiple myeloma data and mature (64-month follow-up) breast cancer data. Results The 5 approaches yielded considerably different outcomes. Incremental mean predicted life-years vary most in the immature multiple myeloma data set. The lognormal distribution (best statistical fit for approaches 1-4) produces survival increments of 3.5 (95% credible interval: 1.4-5.3), 8.5 (3.1-13.0), 3.5 (1.3-5.4), 2.9 (1.1-4.5), and 1.6 (0.4-2.8) years for approaches 1 to 5, respectively. Approach 1 had the highest face validity for all data sets. Uncertainty over parametric distributions was comparable for GPM-adjusted approaches 1, 3, and 4, and much larger for approach 2. Conclusion This study highlights the importance of GPM adjustment, and particularly of incorporating GPM hazards in the log-likelihood function of standard parametric distributions.

Background: Peptidyl arginine deiminase 4 (PAD4) is an enzyme that converts arginine into citrulline. PAD4 is expressed in neutrophils that, when activated, can drive the formation of neutrophil extracellular traps (NETs). Uncontrolled activation of PAD4 and subsequent citrullination of proteins is increasingly recognized as a driver of (auto)immune diseases. Currently, our understanding of PAD4 structure–function relationships and activity control in vivo is incomplete. Aims: To provide the current state‐of‐the‐art on PAD4 structure‐activity relationships and involvement of PAD4 in autoimmune disorders as well as in thrombo‐inflammatory disease. Materials & Methods: Literature review and molecular modelling Results: In this review, we used molecular modelling to generate a three‐dimensional structure of the complete PAD4 molecule. Using our model, we discuss the catalytic conversion of the arginine substrate to citrulline. Besides mechanistic insight into PAD4 function, we give an overview of biological functions of PAD4 and mechanisms that influence its activation. In addition, we discuss the crucial role of PAD4‐mediated citrullination of histones during the formation of NETs. Subsequently, we focus on the role of PAD4‐mediated NET formation and its role in pathogenesis of rheumatoid arthritis, sepsis and (immune‐)thrombosis. Finally, we summarize current efforts to design different classes of PAD4 inhibitors that are being developed for improved treatment of autoimmune disorders as well as thrombo‐inflammatory disease. Discussion: Advances in PAD4 structure‐function are still necessary to gain a complete insight in mechanisms that control PAD4 activity in vivo. The involvement of PAD4 in several diseases signifies the need for a PAD4 inhibitor. Although progress has been made to produce an isotype specific and potent PAD4 inhibitor, currently no PAD4 inhibitor is ready for clinical use. Conclusion: More research into PAD4 structure and function and into the regulation of its activity is required for the development of PAD4 specific inhibitors that may prove vital to combat and prevent autoimmune disorders and (thrombo)inflammatory disease.

Objectives: In Denmark, patients with inflammatory arthritis (IA) have completed patient-reported outcome measures (PROMs) via touchscreens in the outpatient clinic since 2006. However, current technology makes it possible for patients to use their own smartphone via an application (app) developed for the Danish Rheumatology Database (DANBIO). This study aims to evaluate the agreement of PROMs between the DANBIO app and outpatient touchscreen in patients with IA. Method: Patients with IA (rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis) were enrolled in a randomized, crossover, agreement study. Participants answered PROMs through the two device types in a randomized order. Differences in PROM scores with 95% confidence intervals (CIs) were evaluated for similarity according to prespecified equivalence margins. Results: The touchscreen invitation was accepted by 138 patients. Sixty patients (20 with each diagnosis) were included. The difference in Health Assessment Questionnaire Disability Index between the two device types was ���0.007 (95% CI ���0.043 to 0.030); thus, equivalence was demonstrated. In addition, all other PROMs obtained with the two device types were equivalent, except for the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), which was within the limits of minimally clinically important difference (MCID). In total, 78.3% preferred the DANBIO app. Conclusion: In patients with IA, equivalence was demonstrated between two device types for all PROMs except BASDAI; however, BASDAI was within the limits of the MCID. Implementation of the DANBIO app is expected to optimize outpatient visits, thereby improving healthcare for the individual patient and society.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10−10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

Contains fulltext : 232372.pdf (Publisher’s version ) (Closed access) OBJECTIVE: It is generally unknown how the attitudes and beliefs of health care professionals (HCPs) might affect the attitudes, beliefs, and medication-taking behavior of patients with rheumatoid arthritis (RA). This study aims 1) to examine the attitudes, health-related associations (both implicit and explicit), and beliefs of HCPs about conventional disease-modifying antirheumatic drugs, and 2) to assess whether these attitudes, health-related associations, and beliefs of HCPs are associated with those of their patients, with their patients' medication-taking behavior, and disease activity. METHODS: HCPs were recruited from 2 centers that specialized in rheumatology across The Netherlands, and patient recruitment followed. In this observational study, implicit outcomes were measured with single-category implicit association tests, whereas explicit outcomes were measured with a bipolar evaluative adjective scale and the Beliefs About Medicines Questionnaire-Specific. Spearman's rank correlations were used to describe correlations between implicit and explicit measures of the attitudes of HCPs. Multilevel, mixed-effects linear models were used to examine the association of HCP-related characteristics, including the implicit and explicit outcomes of HCPs, with those of their patients, their medication-taking behaviors, and disease activity. RESULTS: Of the 1,659 initially invited patients, 254 patients with RA (mean age 62.8 years, mean disease duration 11.8 years, and 68.1% of the patients were female) who were treated by 26 different HCPs agreed to participate in this study. The characteristics, attitudes, health-related associations, and beliefs about medicines of HCPs were not significantly associated with those of their patients, nor with their medication-taking behaviors or disease activity scores. CONCLUSION: This study demonstrated that the attitudes, health-related associations (as measured both implicitly and explicitly), and beliefs of HCPs were not significantly associated with the attitudes, beliefs, medication-taking behavior, and disease activity of patients with RA. 10 p.

Introduction Facilitators and barriers of adherence to disease-modifying anti-rheumatic drugs (DMARDs) have been identified by patients with inflammatory arthritis earlier. However, the relative importance from the patients’ perspective of these factors is unknown. Knowledge on this ranking might guide the development of interventions and may facilitate targeted communication on adherence. This study aims to examine 1) the relative importance patients attach to facilitators and barriers for DMARDs adherence, and 2) the relationship between patient characteristics and ranking of these factors. Methods One hundred twenty-eight outpatients with inflammatory arthritis; (60% female, mean age 62 years (SD = 12), median disease duration 15 years, IQR (7, 23) participated in a Maximum Difference scaling exercise and ranked 35 items based upon previously identified facilitators and barriers to medication adherence. Hierarchical Bayes estimation was used to compute mean Rescaled Probability Scores (RPS; 0–100) (i.e. relative importance score). Kendall’s coefficient of concordance was used to examine a possible association between patients’ characteristics (i.e. age, sex and educational level) and ranking of the items. Results The three most important items ranked by patients were: Reduction of symptoms formulated as “Arthritis medications help to reduce my symptoms” (RPS = 7.30, CI 7.17–7.44), maintaining independence formulated as “I can maintain my independence as much as possible” (RPS = 6.76, CI 6.54–6.97) and Shared decision making formulated as “I can decide –together with my physician- about my arthritis medications” (RPS = 6.48, CI 6.24–6.72). No associations between patient characteristics and ranking of factors were found. Conclusions Reducing symptoms, maintaining independency and shared decision making are patients’ most important factors for DMARDs adherence. This knowledge might guide the development of interventions and may facilitate communication between health professionals and their patients on medication adherence.

A panel of European experts was convened to establish consensus on a treat-to-target strategy in osteoporosis. Panellists agreed that the ultimate goals of treating osteoporosis are recovering pre-fracture functional level and reducing subsequent fracture risk; there was consensus that total hip bone mineral density is currently the most appropriate treatment target in clinical practice. Introduction A modified Delphi approach was convened to establish consensus among European experts on best practice management for patients with fragility fractures and whether a treat-to-target (T2T) strategy is applicable in osteoporosis. Methods A panel of 12 clinical experts (from eight European countries) voted on 13 final statements relating to a T2T strategy for osteoporosis across three rounds of blinded, remotely conducted electronic surveys (Likert scale: 'strongly disagree', 'disagree', 'unable to answer', 'agree', 'strongly agree'). When panellists disagreed, they were asked how the statement could be adjusted to allow for a positive response, which was used to refine the statement for the following round. Consensus was defined as >= 75% agreement with a statement. Panellists were selected by UCB Pharma, which provided financial and logistical support. Results Consensus was reached for 13/13 statements. Panellists agreed that the most important goals for fragility fracture patients are recovery of pre-fracture functional level and reduction of subsequent fracture risk. There was also consensus that a T2T strategy is applicable to osteoporosis and that bone mineral density (BMD) is currently the most clinically appropriate target. With regard to the definition of a specific BMD treatment target and timeframes applicable to T2T in osteoporosis, no clear consensus was reached; panellists emphasised that these would need to be individually determined. Conclusions According to a panel of European experts, the main goals of fracture management are to recover pre-fracture functional level and reduce fracture risk. Total hip BMD seems to be the most clinically appropriate treatment target within a T2T strategy. This study was sponsored by UCB Pharma and Amgen Inc. Support for study conception and design, acquisition of data, and analysis and interpretation of data, provided by Ogilvy Health, was funded by UCB Pharma and Amgen Inc. Support for third-party writing assistance for this article, provided by Kristian Clausen, MPH, Madeleine Warner, PhD, and Simon Foulcer, PhD, Costello Medical, UK was funded by UCB Pharma and Amgen Inc. in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). Timoshanko, J (corresponding author), UCB Pharma, Slough, Berks, England. jen.timoshanko@ucb.com

Circulating calprotectin is a potential biomarker for endovascular inflammation in type 2 diabetes mellitus (T2DM). We investigated the determinants of calprotectin and its relationship with the presence of cardiovascular disease (CVD) in 362 T2DM patients included in the Diabetes and Lifestyle Cohort Twente-1 (DIALECT-1) study. Lifestyle exposures, including nutrition, were determined by validated questionnaires. CVD was defined as coronary artery diseases, strokes, and peripheral artery diseases. Median serum calprotectin levels were 1.04 mg/L [IQR: 0.73&ndash, 1.46 mg/L] and were higher in women (1.11 mg/L) than men (0.96 mg/L, p = 0.007). Current smoking was a major independent determinant of circulating calprotectin, with a 51% higher calprotectin compared to never smoking (p &lt, 0.001). Albuminuria (p = 0.011), former smoking (p = 0.023), and intake of mono- and disaccharides (p = 0.005) also contributed independently to circulating calprotectin. Each incremental increase in calprotectin level was associated with 1.36-times higher odds for CVD (95% CI 1.04&ndash, 1.77, p = 0.026). In the current study, calprotectin was the only inflammatory parameter significantly associated with CVD. The strong association of circulating calprotectin with smoking, a well-known direct cause of vascular inflammation, and also with CVD, stresses the urge for further research to define its role as a biomarker in T2DM.

The introduction of immunosuppressive therapy for ANCA-associated vasculitis (AAV) has greatly improved outcomes, though patients now accumulate damage from vasculitis activity and adverse effects of treatment. Prediction of treatment outcomes using gene variants might help reduce this damage by allowing for personalized treatment. Several studies have studied genetic polymorphisms in relation to treatment outcomes of AAV. This review gives an overview of these studies, discussing both gene polymorphisms associated with inflammatory pathways (potentially influencing disease outcomes such as activity, severity, and relapse risk) and pharmacogenetics (potentially influencing drug metabolism and/or drug response). Subsequently, potential benefits of testing genetic variants for AAV and the steps needed for its implementation in clinical practice are discussed. The conclusion of this review is that measurement of most polymorphisms is currently not indicated in clinical practice.

SLC2A3 encodes the predominantly neuronal glucose transporter 3 (GLUT3), which facilitates diffusion of glucose across plasma membranes. The human brain depends on a steady glucose supply for ATP generation, which consequently fuels critical biochemical processes, such as axonal transport and neurotransmitter release. Besides its role in the central nervous system, GLUT3 is also expressed in nonneural organs, such as the heart and white blood cells, where it is equally involved in energy metabolism. In cancer cells, GLUT3 overexpression contributes to the Warburg effect by answering the cell's increased glycolytic demands. The SLC2A3 gene locus at chromosome 12p13.31 is unstable and prone to non‐allelic homologous recombination events, generating multiple copy number variants (CNVs) of SLC2A3 which account for alterations in SLC2A3 expression. Recent associations of SLC2A3 CNVs with different clinical phenotypes warrant investigation of the potential influence of these structural variants on pathomechanisms of neuropsychiatric, cardiovascular, and immune diseases. In this review, we accumulate and discuss the evidence how SLC2A3 gene dosage may exert diverse protective or detrimental effects depending on the pathological condition. Cellular states which lead to increased energetic demand, such as organ development, proliferation, and cellular degeneration, appear particularly susceptible to alterations in SLC2A3 copy number. We conclude that better understanding of the impact of SLC2A3 variation on disease etiology may potentially provide novel therapeutic approaches specifically targeting this GLUT.

Background Clinical manifestations of sarcoidosis vary widely, depending on the intensity of the inflammation and the organ systems affected. So far, no curative treatment exists; the disease can only be suppressed. All treatment options cause side effects affecting quality of life. The aim of this study was to establish and rank the prevalence of self-reported gastrointestinal side effects of drugs used in the treatment of sarcoidosis. Methods A cross-sectional web-based anonymous survey about complaints and side effects was conducted among sarcoidosis patients in the Netherlands, United Kingdom, and United States of America. Results Of the participants, 70% were being treated with one or more drugs. The most important reported side effect was weight gain, associated with increased appetite among prednisone users (as monotherapy as well as in combination with other drugs). Methotrexate (MTX) users especially experienced nausea, with monotherapy as well as combination therapy. Vomiting and weight loss were most prominent among azathioprine and mycophenolate mofetil (MMF) users, whereas diarrhoea was frequently mentioned by MMF and MTX users. The reported side effects of hydroxychloroquine were generally rather mild. Conclusion The current study ranked the gastrointestinal side effects associated with pharmacotherapy in sarcoidosis patients. Pharmacotherapy does have multiple gastrointestinal side effects. The strongest association between a reported side effect and drug use was that of weight gain associated with increased appetite among prednisone users. It would therefore be useful for future research to look further into dietary interventions to counter these side effects and reduce their burden.

International audience; In eukaryotic cells, the balance between the synthesis and the degradation decides the steady-state levels of messenger RNAs (mRNA). The removal of adenosine residues from the poly(A) tail, called deadenylation, is the first and the most crucial step in the process of mRNA degradation. Poly (A)-specific ribonuclease (PARN) is one such enzyme that catalyses the process of deadenylation. Although PARN has been primarily known as the regulator of the mRNA stability, recent evidence clearly suggests several other functions of PARN, including a role in embryogenesis, oocyte maturation, cell-cycle progression, telomere biology, non-coding RNA maturation and ribosome biogenesis. Also, deregulated PARN activity is shown to be a hallmark of specific disease conditions. Pathogenic variants in the RN gene have been observed in various cancers and inherited bone marrow failure syndromes. The focus in this review is to highlight the emerging functions of PARN, particularly in the context of human diseases.

Aim To study cell‐mediated immunity in the feet of people with type 2 diabetes with polyneuropathy. Methods In a cohort comprising people with type 2 diabetes with polyneuropathy (n = 17) and without polyneuropathy (n = 12) and a healthy control group (n = 12) indurations due to delayed‐type hypersensitivity responses to intracutaneous Candida albicans antigen were determined in the foot and compared with those in the arm (an area relatively spared in diabetic polyneuropathy). The sizes of indurations on the foot were correlated with electromyographic measurements in the participants with diabetes. Results No differences were observed in the median size of indurations between the foot and arm in healthy controls and participants without polyneuropathy; in participants with polyneuropathy, induration sizes on the foot were smaller than on the arm: 0 (95% CI 0 to 1) vs 5 (95% CI 2 to 6) mm (P < 0.01). In participants with diabetes, larger indurations correlated with better nerve function (Spearman's rho 0.35 to 0.39). Conclusion Our findings suggest that diabetic peripheral polyneuropathy negatively affects cell‐mediated immunity in the foot. (Clinical Trials registry no.: NCT01370837), What's new? Local immune responses can be impaired as a result of neurological deficits.Diabetic peripheral neuropathy could negatively affect cell‐mediated immunity selectively in the foot, the site most frequently and severely affected by peripheral neuropathy.More severe impairment of cell‐mediated immunity correlates with worse peripheral nerve function as measured by electromyography.Our study is the first to suggest the presence of locally diminished cell‐mediated immunity in the foot in people with diabetic peripheral neuropathy.Impaired cellular immunity in the foot may explain the paucity of signs of inflammation in diabetic foot infections.

Objective.The Outcome Measures in Rheumatology (OMERACT) Shared Decision Making (SDM) Working Group aims to determine the core outcome domain set for measuring the effectiveness of SDM interventions in rheumatology trials.Methods.A white paper was developed to clarify the draft core domain set. It was then used to prepare for interviews to investigate reasons for lack of consensus on it and to suggest further improvements.Results.OMERACT scientists/clinicians (n = 13) and patients (n = 10) suggested limiting the core domain set to outcome domains, removing process domains, and clarifying remaining domains.Conclusion.A revised core domain set will undergo further consensus-building.

AIMS: To investigate whether an international consensus exists among TMD experts regarding indications, performance, follow-up, and effectiveness of jaw exercises. METHODS: A questionnaire with 31 statements regarding jaw exercises was constructed. Fourteen international experts with some geographic dispersion were asked to participate in this Delphi study, and all accepted. The experts were asked to respond to the statements according to a 5-item verbal Likert scale that ranged from "strongly agree" to "strongly disagree." The experts could also leave free-text comments, which was encouraged. After the first round, the experts received a compilation of the other experts' earlier responses. Some statements were then rephrased and divided to clarify the essence of the statement. Subsequently, the experts were then asked to answer the questionnaire (32 statements) again for the second round. Consensus was set to 80% agreement or disagreement. RESULTS: There is consensus among TMD experts that jaw exercises are effective and can be recommended to patients with myalgia in the jaw muscles, restricted mouth opening capacity due to hyperactivity in the jaw closing muscles, and disc displacement without reduction. The patients should always be instructed in an individualized jaw exercise program and also receive both verbal advice and written information about the treatment modality. CONCLUSION: This Delphi study showed that there is an international consensus among TMD experts that jaw exercises are an effective treatment and can be recommended to patients with TMD pain and disturbed jaw function. ispartof: JOURNAL OF ORAL & FACIAL PAIN AND HEADACHE vol:33 issue:4 pages:389-398 ispartof: location:United States status: published

Background To determine the serum levels of the lectin pathway proteins early in the disease course and 17 years after disease onset and to correlate the protein levels to markers of disease activity in participants from a population-based Nordic juvenile idiopathic arthritis (JIA) cohort. Additionally, to assess the predictive value of lectin pathway proteins with respect to remission status. Methods A population-based cohort study of consecutive cases of JIA with a disease onset from 1997 to 2000 from defined geographical areas of Finland, Sweden, Norway and Denmark with 17 years of follow-up was performed. Clinical characteristics were registered and H-ficolin, M-ficolin, MASP-1, MASP-3, MBL and CL-K1 levels in serum were analyzed. Results In total, 293 patients with JIA were included (mean age 23.7 ± 4.4 years; mean follow-up 17.2 ± 1.7 years). Concentrations of the lectin protein levels in serum were higher at baseline compared to the levels 17 years after disease onset (p ≤ 0.006, n = 164). At baseline, the highest level of M-ficolin was observed in systemic JIA. Further, high M-ficolin levels at baseline and at 17-year follow-up were correlated to high levels of ESR. In contrast, high MASP-1 and MASP-3 tended to correlate to low ESR. CL-K1 showed a negative correlation to JADAS71 at baseline. None of the protein levels had prognostic abilities for remission status 17 years after disease onset. Conclusion We hypothesize that increased serum M-ficolin levels are associated with higher disease activity in JIA and further, the results indicate that MASP-1, MASP-3 and CL-K1 are markers of inflammation.

Interleukin-1 beta (IL-1 beta) plays a central role in the induction of rheumatoid arthritis (RA). In the present study, we demonstrated that lipidoid-polymer hybrid nanoparticle (FS14-NP) can efficiently deliver siRNA against IL-1 beta (siIL-1 beta) to macrophages and effectively suppress the pathogenesis of experimental arthritis induced by collagen antibody (CAIA mice). FS14-NP/siIL-1 beta achieved approximately 70% and 90% genesilencing efficiency in the RAW 264.7 cell line and intraperitoneal macrophages, respectively. Intravenous administration of FS14-NP/siRNA led to rapid accumulation of siRNA in macrophages within the arthritic joints. Furthermore, FS14-NP/siIL1 beta treatment lowered the expression of pro-inflammatory cytokines in arthritic joints and dramatically attenuated ankle swelling, bone erosion, and cartilage destruction. These results demonstrate that FS14-NP/siIL-1 beta may represent an effective therapy for systemic arthritis and other inflammatory disorders.

Since the end of the 1990s, several multisegment foot models (MSFMs) have been developed. Several models were used to describe foot and ankle kinematics in patients with foot and ankle pathologies; however, the diagnostic value for clinical practice of these models is not known. This review searched in the literature for studies describing kinematics in patients after foot and ankle trauma using an MSFM. The diagnostic value of the MSFMs in patients after foot and ankle trauma was also investigated. A search was performed on the databases PubMed/MEDLINE, Embase, and Cochrane Library. To investigate the diagnostic value of MSFMs in patients after foot and ankle trauma, studies were classified and analyzed following the diagnostic research questions formulated by Knottnerus and Buntinx. This review was based on 7 articles. All studies were published between 2010 and 2015. Five studies were retrospective studies, and 2 used an intervention. Three studies described foot and ankle kinematics in patients after fractures. Four studies described foot and ankle kinematics in patients after ankle sprain. In all included studies, altered foot and ankle kinematics were found compared with healthy subjects. No results on patient outcome using MSFMs and costs were found. Seven studies were found reporting foot and ankle kinematics in patients after foot and ankle trauma using an MSFM. Results show altered kinematics compared with healthy subjects, which cannot be seen by other diagnostic tests and add valuable data to the present literature; therefore, MSFMs seem to be promising diagnostic tools for evaluating foot and ankle kinematics. More research is needed to find the additional value for MSFMs regarding patient outcome and costs. (C) 2018 by the American College of Foot and Ankle Surgeons. All rights reserved.

Excessive or inappropriate inflammatory responses can cause serious and even fatal diseases. The CCAAT/enhancer-binding protein alpha (CEBPA) gene encodes C/EBPα, a transcription factor that plays a fundamental role in controlling maturation of the myeloid lineage and is also expressed during the late phase of inflammatory responses when signs of inflammation are decreasing. MTL-CEBPA, a small activating RNA targeting for upregulation of C/EBPα, is currently being evaluated in a phase 1b trial for treatment of hepatocellular carcinoma. After dosing, subjects had reduced levels of pro-inflammatory cytokines, and we therefore hypothesized that MTL-CEBPA has anti-inflammatory potential. The current study was conducted to determine the effects of C/EBPα saRNA - CEBPA-51 - on inflammation in vitro and in vivo after endotoxin challenge. CEBPA-51 led to increased expression of the C/EBPα gene and inhibition of pro-inflammatory cytokines in THP-1 monocytes previously stimulated by E. coli-derived lipopolysaccharide (LPS). Treatment with MTL-CEBPA in an LPS-challenged humanized mouse model upregulated C/EBPα mRNA, increased neutrophils, and attenuated production of several key pro-inflammatory cytokines, including TNF-α, IL-6, IL-1β, and IFN-γ. In addition, a Luminex analysis of mouse serum revealed that MTL-CEBPA reduced pro-inflammatory cytokines and increased the anti-inflammatory cytokine IL-10. Collectively, the data support further investigation of MTL-CEBPA in acute and chronic inflammatory diseases where this mechanism has pathogenic importance., MTL-CEBPA is a small activating RNA that targets the upregulation of transcription factor C/EBPα, currently being evaluated in a phase 1b trial for treatment of hepatocellular carcinoma. Zhou et al. demonstrate that MTL-CEBPA increases the expression of C/EBPα and displays anti-inflammatory effects in a tissue culture system and a humanized mouse model.

BackgroundIdiopathic paediatric uveitis (IPU) and juvenile idiopathic arthritis associated uveitis (JIA-U) are the two most common entities in paediatric uveitis. This study addressed the possible association of IPU and JIA-U with genes that had been shown earlier to be associated with juvenile idiopathic arthritis.MethodsWe carried out a case-control association study involving 286 IPU, 134 JIA-U patients and 743 healthy individuals. A total of 84 candidate single nucleotide polymorphisms (SNPs) in 60 genes were selected for this study. The MassARRAY platform and iPLEX Gold Genotyping Assay was used to genotype 83 candidate SNPs and the remaining SNP (rs27293) was analysed using the TaqMan SNP Genotyping Assay.ResultsNo evidence was found for an association of the candidate polymorphisms tested with IPU. Six SNPs (PRM1/rs11074967, JAZF1/rs73300638, IRF5/rs2004640, MEFV/rs224217, PSMA3/rs2348071 and PTPN2/rs7234029) showed an association with JIA-U (p−2).ConclusionOur findings showed associations of six SNPs (PRM1/rs11074967, JAZF1/rs73300638, IRF5/rs2004640, MEFV/rs224217, PSMA3/rs2348071 and PTPN2/rs7234029) with JIA-U. No association was detected between the 84 tested SNPs and IPU.

PurposeThe purpose of this study was to assess test-retest reliability, agreement, and responsiveness of questionnaires on productivity loss (iPCQ-VR) and healthcare utilization (TiCP-VR) for sick-listed workers with chronic musculoskeletal pain who were referred to vocational rehabilitation. Methods Test-retest reliability and agreement was assessed with a 2-week interval. Responsiveness was assessed at discharge after a 15-week vocational rehabilitation (VR) program. Data was obtained from six Dutch VR centers. Test-retest reliability was determined with intraclass correlation coefficient (ICC) and Cohen's kappa. Agreement was determined by Standard Error of Measurement (SEM), smallest detectable changes (on group and individual level), and percentage observed, positive and negative agreement. Responsiveness was determined with area under the curve (AUC) obtained from receiver operation characteristic (ROC). Results A sample of 52 participants on test-retest reliability and agreement, and a sample of 223 on responsiveness were included in the analysis. Productivity loss (iPCQ-VR): ICCs ranged from 0.52 to 0.90, kappa ranged from 0.42 to 0.96, and AUC ranged from 0.55 to 0.86. Healthcare utilization (TiCP-VR): ICC was 0.81, and kappa values of the single healthcare utilization items ranged from 0.11 to 1.00. Conclusions The iPCQ-VR showed good measurement properties on working status, number of hours working per week and long-term sick leave, and low measurement properties on short-term sick leave and presenteeism. The TiCP-VR showed adequate reliability on all healthcare utilization items together and medication use, but showed low measurement properties on the single healthcare utilization items.

Funding Information: Supported by the Helsinki University Hospital , the Sigrid Juselius Foundation , the Academy of Finland , Finska Läkaresällskapet , the Research and Science Foundation of Farmos , The Paulo Foundation , Jalmari and Rauha Ahokas Foundation , Aarne Koskelo Foundation , Päivi and Sakari Sohlberg Foundation , Finnish Pulmonary Association , Biomedicum Helsinki Foundation , Jane and Aatos Erkko Foundation , and the University of Helsinki . Funding Information: Supported by the Helsinki University Hospital, the Sigrid Juselius Foundation, the Academy of Finland, Finska L?kares?llskapet, the Research and Science Foundation of Farmos, The Paulo Foundation, Jalmari and Rauha Ahokas Foundation, Aarne Koskelo Foundation, P?ivi and Sakari Sohlberg Foundation, Finnish Pulmonary Association, Biomedicum Helsinki Foundation, Jane and Aatos Erkko Foundation, and the University of Helsinki. Publisher Copyright: © 2022 American Society for Investigative Pathology Obliterative bronchiolitis (OB) after lung transplantation is a nonreversible, life-threatening complication. Herein, the role of vascular endothelial growth factor receptor (Vegfr)-1 and -2 was investigated in the development of obliterative airway disease (OAD), an experimental model for OB. The nonimmunosuppressed recipients underwent transplantation with fully major histocompatibility complex mismatched heterotopic tracheal allografts and received Vegfr1 and -2-specific monoclonal antibodies either alone or in combination, or rat IgG as a control. The treatment with Vegfr1- or -2-blocking antibody significantly decreased intragraft mRNA expression of natural killer cell activation markers early after transplantation. This was followed by reduced infiltration of Cd11b thorn cells and Cd4 thorn T cells as well as down-regulated mRNA expression of proinflammatory chemokines and profibrotic growth factors. However, blocking of both Vegfr1 and -2 was necessary to reduce luminal occlusion. Furthermore, concomitant inhibition of the calcineurin activation pathway almost totally abolished the development of OAD. This study proposes that blocking of Vegf receptors blunted natural killer cell and innate immune responses early after transplantation and attenuated the development of OAD. The results of this study suggest that further studies on the role of Vegfr1 and -2 blocking in development of obliterative airway lesions might be rewarding. (Am J Pathol 2022, 192: 254-269; https://doi.org/10.1016/ j.ajpath.2021.10.018)

The generation of post-translational modifications (PTMs) in human proteins is a physiological process leading to structural and immunologic variety in proteins, with potentially altered biological functions. PTMs often arise through normal responses to cellular stress, including general oxidative changes in the tissue microenvironment and intracellular stress to the endoplasmic reticulum or immune-mediated inflammatory stresses. Many studies have now illustrated the presence of 'neoepitopes' consisting of PTM self-proteins that induce robust autoimmune responses. These pathways of inflammatory neoepitope generation are commonly observed in many autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes (T1D), among others. This review will focus on one specific PTM to self-proteins known as citrullination. Citrullination is mediated by calcium-dependent peptidylarginine deiminase (PAD) enzymes, which catalyze deimination, the conversion of arginine into the non-classical amino acid citrulline. PADs and citrullinated peptides have been associated with different autoimmune diseases, notably with a prominent role in the diagnosis and pathology of rheumatoid arthritis. More recently, an important role for PADs and citrullinated self-proteins has emerged in T1D. In this review we will provide a comprehensive overview on the pathogenic role for PADs and citrullination in inflammation and autoimmunity, with specific focus on evidence for their role in T1D. The general role of PADs in epigenetic and transcriptional processes, as well as their crucial role in histone citrullination, neutrophil biology and neutrophil extracellular trap (NET) formation will be discussed. The latter is important in view of increasing evidence for a role of neutrophils and NETosis in the pathogenesis of T1D. Further, we will discuss the underlying processes leading to citrullination, the genetic susceptibility factors for increased recognition of citrullinated epitopes by T1D HLA-susceptibility types and provide an overview of reported autoreactive responses against citrullinated epitopes, both of T cells and autoantibodies in T1D patients. Finally, we will discuss recent observations obtained in NOD mice, pointing to prevention of diabetes development through PAD inhibition, and the potential role of PAD inhibitors as novel therapeutic strategy in autoimmunity and in T1D in particular. ispartof: FRONTIERS IN IMMUNOLOGY vol:12 ispartof: location:Switzerland status: published

[Abstract] Objective: Synovial inflammation is one of the most characteristic events in different types of arthritis, including Osteoarthritis (OA). Emerging evidence also suggests the involvement of lipids in the regulation of inflammatory processes. The aim of this study was to elucidate the heterogeneity and spatial distribution of lipids in the OA synovial membrane and explore their putative involvement in inflammation. Method: The abundance and distribution of lipids were examined in human synovial membranes. To this end, histological cuts from this tissue were analysed by matrix-assisted laser desorption ionization - mass spectrometry imaging (MALDI-MSI). The lipidomic profile of OA synovium was characterized and compared with healthy and other forms of inflammatory arthropathies as Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) using principal component analysis and discriminant analysis methods. Lipid identification was undertaken by tandem MS analyses and database queries. Results: Our results reveal differential and characteristic lipidomic profiles between OA and control samples. Specifically, we unveiled that OA synovium presents elevated levels of phosphatidylcholines, fatty acids and lysophosphatidic acids and lower levels of lysophosphatidylcholines compared to control tissues. The spatial distribution of particular glycerophospholipids was also correlated with hypertrophic, inflamed or vascularized synovial areas. Compared with other inflammatory arthritis, the OA tissue showed lower amounts of phosphatidylethanolamine-based plasmalogens. Conclusions: This study provides a novel insight into the lipid profiles of synovial membrane and differences in abundance between OA and control tissues. The lipidomic alterations improves understanding of the pathogenic mechanisms of OA and may be important for its diagnosis. This work is supported by grants from Fondo Investigación Sanitaria-Spain (PI16/02124, PI17/00404 PI19/01206 and RETIC-RIER-RD16/0012/0002), integrated in the National Plan for Scientific Program, Development and Technological Innovation 2013–2016 and funded by the ISCIII-General Subdirection of Assessment and Promotion of Research – European Regional Development Fund (FEDER) “A way of making Europe”. This study is also supported by AE CICA-INIBIC (ED431E 2018/03) and grants IN607A2017/11 and IN607D2020/10 from Xunta de Galicia. The Biomedical Research Networking Center (CIBER) is an initiative from Instituto de Salud Carlos III (ISCIII). The Proteomics Unit of GIR belongs to ProteoRed, PRB3- ISCIII (PT17/0019/0014). B.R. has been supported by Xunta de Galicia (IN606B-2016/004). The research was partially performed within the M4I research program, financially supported by the Dutch Province of Limburg as part of the “LINK” program Xunta de Galicia; ED431E 2018/03 Xunta de Galicia; IN607A2017/11 Xunta de Galicia; IN607D2020/10 Xunta de Galicia; IN606B-2016/004

BackgroundClinical studies with work participation (WP) as an outcome domain pose particular methodological challenges that hamper interpretation, comparison between studies and meta-analyses.ObjectivesTo develop Points to Consider (PtC) for design, analysis and reporting of studies of patients with inflammatory arthritis that include WP as a primary or secondary outcome domain.MethodsThe EULAR Standardised Operating Procedures were followed. A multidisciplinary taskforce with 22 experts including patients with rheumatic diseases, from 10 EULAR countries and Canada, identified methodologic areas of concern. Two systematic literature reviews (SLR) appraised the methodology across these areas. In parallel, two surveys among professional societies and experts outside the taskforce sought for additional methodological areas or existing conducting/reporting recommendations. The taskforce formulated the PtC after presentation of the SLRs and survey results, and discussion. Consensus was obtained through informal voting, with levels of agreement obtained anonymously.ResultsTwo overarching principles and nine PtC were formulated. The taskforce recommends to align the work-related study objective to the design, duration, and outcome domains/measurement instruments of the study (PtC: 1–3); to identify contextual factors upfront and account for them in analyses (PtC: 4); to account for interdependence of different work outcome domains and for changes in work status over time (PtC: 5–7); to present results as means as well as proportions of patients reaching predefined meaningful categories (PtC: 8) and to explicitly report volumes of productivity loss when costs are an outcome (PtC:9).ConclusionAdherence to these EULAR PtC will improve the methodological quality of studies evaluating WP.

Genome wide association, epidemiological, and clinical studies have established high lipoprotein(a) [Lp(a)] as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Lp(a) is an apoB100 containing lipoprotein covalently bound to apolipoprotein(a) [apo(a)], a glycoprotein. Plasma Lp(a) levels are to a large extent determined by genetics. Its link to cardiovascular disease (CVD) may be driven by its pro-inflammatory effects, of which its association with oxidized phospholipids (oxPL) bound to Lp(a) is the most studied. Various inflammatory conditions, such as rheumatoid arthritis (RA), systemic lupus erythematosus, acquired immunodeficiency syndrome, and chronic renal failure are associated with high Lp(a) levels. In cases of RA, high Lp(a) levels are reversed by interleukin-6 receptor (IL-6R) blockade by tocilizumab, suggesting a potential role for IL-6 in regulating Lp(a) plasma levels. Elevated levels of IL-6 and IL-6R polymorphisms are associated with CVD. Therapies aimed at lowering apo(a) and thereby reducing plasma Lp(a) levels are in clinical trials. Their results will determine if reductions in apo(a) and Lp(a) decrease cardiovascular outcomes. As we enter this new arena of available treatments, there is a need to improve our understanding of mechanisms. This review will focus on the role of Lp(a) in inflammation and CVD.

Objective The aim was systematically to identify and evaluate factors related to fatigue in individuals with hip and/or knee OA. Methods A systematic literature search was conducted using AMED, CINAHL, MEDLINE, ProQuest and Web of Science Core Collections databases. Inclusion criteria comprised cross-sectional, case–control or longitudinal studies on patients with a diagnosis of hip and/or knee OA that included self-reported fatigue measures. Study quality was assessed using the National Heart, Lung and Blood Institute quality appraisal tool, and factors were synthesized within a bio-behavioural framework. Study designs and quality were combined to determine current evidence levels using best evidence synthesis grading. The full review protocol is available from PROSPERO (PROSPERO 2019: CRD42019138571). Results Twenty-four studies were included, of which 19 were high, 4 moderate and 1 low quality. There was strong evidence of an association between poor self-reported physical function and high depressive symptoms with higher fatigue. Moderate evidence of an association was found between severe pain, high numbers of co-morbidities and low physical activity levels with higher fatigue. There was moderate or limited evidence of no association between most sociodemographic factors and radiographic OA severity with fatigue. Conclusion Targets for fatigue management might include improving physical function, reducing depressive symptoms, pain and co-morbidities, and increasing physical activity levels. There is a need for more rigorous longitudinal studies to understand the causal effect of fatigue determinants within the hip and knee OA populations.

The dual anticytokine and antiviral actions of baricitinib reduce SARS-CoV-2 infectivity in organoids and morbidity in people., Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.

Over the years, a wide variety of therapeutic antibodies has been successfully introduced in the auto-immunology clinic, and many more are on the way. Many of these treatments address either a pathogenic circulating molecule or a cell-bound molecule. Whereas addressing the former target results in neutralization of the soluble factor and binding to the latter target either inhibits cellular function or induces selective cell death. If this targeted molecule or cell is part of the immune system, this therapy evokes a state of immunodeficiency with infections as a possible consequence. Therefore, immune monitoring is needed to prevent such adverse side effects of immunotherapy. In this paper, different immunotherapies used in Sjögren’s syndrome, as well as different approaches to monitoring the immune system, are discussed.

Cardiometabolic comorbidities are highly prevalent in clinical populations, and have been associated (partly) with their sedentary lifestyle. Although lifestyle interventions targeting sedentary behaviour (SB) have been studied extensively in the general population, the effect of such strategies in clinical populations is not yet clear. Therefore, this systematic review and meta-analysis evaluated the effect of different lifestyle interventions on SB and cardiometabolic health in clinical populations. Randomised controlled trials were collected from five bibliographic databases (PubMed, Embase, Web of Science, The Cochrane Central Register of Controlled Trials, and Scopus). Studies were eligible for inclusion if they evaluated a lifestyle intervention to reduce objectively measured SB, in comparison with a control intervention among persons with a clinical condition. Data were pooled using a random-effects meta-analysis. In total, 7094 studies were identified. Eighteen studies met the inclusion criteria and were categorised in five population groups: overweight/obesity, type 2 diabetes mellitus, cardiovascular, neurological/cognitive and musculoskeletal diseases. Participants reduced their SB by 64 min/day (95%CI: [-91, -38] min/day; p < 0.001), with larger within-group differences of multicomponent behavioural interventions including motivational counselling, self-monitoring, social facilitation and technologies (-89 min/day; 95%CI: [-132, -46] min/day; p < 0.001). Blood glycated haemoglobin concentration (-0.17%; 95% CI: [-0.30, -0.04]%; p = 0.01), fat percentage (-0.66%; 95% CI: [-1.26, -0.06]%, p = 0.03) and waist circumference (-1.52 cm; 95%CI: [-2.84, -0.21] cm; p = 0.02) were significantly reduced in the intervention groups compared to control groups. Behavioural lifestyle interventions reduce SB among clinical populations and improve cardiometabolic risk markers such as waist circumference, fat percentage, and glycaemic control. Sedentary behaviour, Cardiometabolic health, Clinical populations.

ObjectivesHealthcare professionals other than rheumatologists experience difficulties in detecting early inflammatory arthritis (IA) by joint examination. Self-reported symptoms are increasingly considered as helpful and could be incorporated in online tools to assist healthcare professionals, but first their discriminative ability must be assessed. As part of this effort, we evaluated whether inquiring about functional impairments could aid early IA identification.DesignCross-sectional derivation and validation study.SettingData from two Early Arthritis Recognition Clinics (EARC) in the Netherlands were studied, which are easy access outpatient rheumatology clinics intermediary between primary and secondary care for patients in whom general practitioners suspect but are unsure about IA presence.ParticipantsBetween 2010 and 2014, 997 patients consecutively visited the Leiden-EARC (derivation cohort). Patients consecutively visiting the Groningen EARC (2010–2014, n=506) and Leiden-EARC (2015–2018, n=557) served as validation cohorts.Primary and secondary outcome measuresPhysical functioning was assessed with the Health Assessment Questionnaire Disability-Index (HAQ); IA presence by physical joint examination by rheumatologists. HAQ questions were studied individually regarding discriminative ability for IA presence. For the best discriminating question, ORs and positive predictive values (PPVs) for IA presence were determined.ResultsIA was ascertained in 43% (derivation cohort), 53% and 35% (validation cohorts). In the derivation cohort, IA presence associated with higher mean HAQ scores (0.84 vs 0.73, p=0.003). One question on difficulties with dressing equalled discriminative ability of the total HAQ score. ‘Difficulties with dressing’ yielded ORs for IA presence of 1.8 (95% CI 1.4 to 2.4) in the derivation cohort; 2.0 (1.4 to 2.9) and 2.1 (1.5 to 3.1) in the validation cohorts. After adjustments for clinical characteristics these were 1.7 (1.3 to 2.3), 1.6 (1.1 to 2.5) and 1.9 (1.2 to 2.9). PPVs (probabilities of IA for positive answers) ranged 42%–60% and negative predictive values (probabilities of no IA for negative answers) ranged 57%–74%.ConclusionsPatient-reported difficulties with dressing in patients with suspected IA associated with actual IA presence. Although further validation is required, for example, in primary care, this simple question could be of help in future early IA detection tools for healthcare professionals with limited experience in joint examination.

Background Several studies have stated that TNF-α participates in the pathogenesis of scleritis, but also in several systemic autoimmune diseases and vasculitis, of which some are associated with scleritis. Earlier GWAS and SNP studies have confirmed that multiple SNPs of TNF related genes are associated with many immune-mediated disorders. The purpose of this study was to examine the association of TNF related gene polymorphisms with scleritis in Chinese Han. A case-control study was carried out in 556 non-infectious scleritis cases and 742 normal controls. A total of 28 single-nucleotide polymorphisms (SNPs) were genotyped by the iPLEXGold genotyping assay. Results No significant correlations were seen between the individual SNPs in the TNF related genes and scleritis. Haplotype analysis showed a significantly decreased frequency of a TNFAIP3 TGT haplotype (order of SNPs: rs9494885, rs3799491, rs2230926) (Pc = 0.021, OR = 0.717, 95% CI = 0.563–0.913) and a significantly increased frequency of a TNFSF4 GT haplotype (order of SNPs: rs3850641, rs704840) (Pc = 0.004, OR = 1.691, 95% CI = 1.205–2.372) and TNFSF15 CCC haplotype (order of SNPs: rs6478106, rs3810936, rs7865494) (Pc = 0.012, OR = 1.662, 95% CI = 1.168–2.363) in patients with scleritis as compared with healthy volunteers. Conclusions This study reveals that a TGT haplotype in TNFAIP3 may be a protective factor for the development of scleritis and that a GT haplotype in TNFSF4 and a CCC haplotype in TNFSF15 may be risk factors for scleritis in Chinese Han.

BackgroundImmunogenicity of tumor necrosis factor alpha inhibitors (TNFis) has been recognized as an important problem that may cause loss of efficacy and adverse events such as infusion reactions. TNFis are being increasingly used among patients with Behçet syndrome (BS) and scarce data exist on this topic.ObjectiveWe aimed to investigate the prevalence of anti-infliximab (IFX) antibodies in patients with Behçet syndrome together with suitable controls.MethodsWe collected serum samples from 66 consecutive Behçet syndrome patients (51 M, 15 F, mean age 37 ± 9 years) who were treated with IFX. Additionally, similarly treated 27 rheumatoid arthritis, 53 ankylosing spondylitis, 25 Crohn’s disease patients, and 31 healthy subjects were included as controls. Samples were collected just before an infusion, stored at −80°C until analysis, and serum IFX trough levels and anti-IFX antibodies were measured by ELISA. We used a cut-off value of 1 μg/ml for serum IFX trough level, extrapolating from rheumatoid arthritis studies.ResultsAnti-IFX antibodies were detected in four (6%) Behçet syndrome, five (18.5%) rheumatoid arthritis, three (12%) Crohn’s disease, and one (2%) ankylosing spondylitis patient. The median serum IFX trough level was significantly lower in patients with anti-IFX antibodies compared to those without antibodies [2.32 (IQR: 0.6–3.6) vs. 3.35 (IQR: 1.63–5.6); p = 0.019]. The serum IFX trough level was lower than the cut-off value in 6/13 (46%) patients with anti-IFX antibodies and in 25/158 (16%) patients without anti-IFX antibodies (p = 0.015). Among the four Behçet syndrome patients with anti-IFX antibodies, two experienced relapses and two had infusion reactions.ConclusionsImmunogenicity does not seem to be a frequent problem in Behçet syndrome patients treated with IFX, but may be associated with relapses and infusion reactions, when present.

Background Biologic treatments impose a large financial burden on healthcare payers. Subcutaneous formulations of trastuzumab and rituximab offer administration cost savings relative to the intravenous products through reduced preparation and infusion times. However, intravenous biosimilars have the potential to offset administration costs through lower drug costs. Objective The objective was to develop a budget impact model (BIM) from a payer’s perspective for the EU-5 countries (UK, France, Germany, Spain, Italy) to demonstrate the economic impact of using intravenous trastuzumab and rituximab biosimilars. Methods An incidence-based BIM was developed to estimate the net budget impact utilising epidemiology data from the literature, market research data on the use of relevant treatments in all approved indications, and corresponding costs. The budget impact was estimated for 5 years following introduction of the biosimilars. Results Analysis using the base-case results indicated that adoption of the biosimilars trastuzumab and rituximab would result in net cost savings. At year 5, the net budget saving ranged from €4.05 million to 303.86 million for rituximab and from €19 million to 172 million for trastuzumab. The cost saving could potentially extend treatment to 291–15,671 more patients with rituximab and 622–3688 more patients with trastuzumab. Conclusion This budget impact analysis emphasised that increased use of intravenous rituximab and trastuzumab biosimilars may result in cost savings from the payer’s perspective across the EU-5 countries. Supplementary Information The online version contains supplementary material available at 10.1007/s40259-020-00461-8.

B cells have classically been recognized for their unique and indispensable role in the production of antibodies. Their potential as immunoregulatory cells with anti-inflammatory functions has received increasing attention during the last two decades. Herein, we highlight pioneering studies in the field of regulatory B cell (Breg) research. We will review the literature on Bregs with a particular focus on their role in the regulation of allergic inflammation. Novartis Forschungsstiftung Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (320030-15987/310030‐179428) Promedica Stiftung Sean N. Parker Center for Allergy and Asthma Research, Stanford University

Contains fulltext : 251829.pdf (Publisher’s version ) (Open Access) OBJECTIVE: There is a lack of real-life studies on interleukin-17 (IL-17) inhibition in psoriatic arthritis (PsA). We assessed real-life 6- and 12-month effectiveness (i.e., retention, remission, low disease activity [LDA], and response rates) of the IL-17 inhibitor secukinumab in PsA patients overall and across 1) number of prior biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), 2) years since diagnosis, and 3) European registries. METHODS: Thirteen quality registries in rheumatology participating in the European Spondyloarthritis Research Collaboration Network provided longitudinal, observational data collected as part of routine care for secondary use. Data were pooled and analyzed with Kaplan-Meier plots, log rank tests, Cox regression, and multiple linear and logistic regression analyses. RESULTS: A total of 2,017 PsA patients started treatment with secukinumab between 2015 and 2018. Overall secukinumab retention rates were 86% and 76% after 6 and 12 months, respectively. Crude (LUNDEX adjusted) 6-month remission/LDA (LDA including remission) rates for the 28-joint Disease Activity Index for Psoriatic Arthritis, the Disease Activity Score in 28 joints using the C-reactive protein level, and the Simplified Disease Activity Index (SDAI) were 13%/46% (11%/39%), 36%/55% (30%/46%), and 13%/56% (11%/47%), and 12-month rates were 11%/46% (7%/31%), 39%/56% (26%/38%), and 16%/62% (10%/41%), respectively. Clinical Disease Activity Index remission/LDA rates were similar to the SDAI rates. Six-month American College of Rheumatology 20%/50%/70% improvement criteria responses were 34%/19%/11% (29%/16%/9%); 12-month rates were 37%/21%/11% (24%/14%/7%). Secukinumab effectiveness was significantly better for b/tsDMARD-naive patients, similar across time since diagnosis (4 years), and varied significantly across the European registries. CONCLUSION: In this large real-world study on secukinumab treatment in PsA, 6- and 12-month effectiveness was comparable to that in previous observational studies of tumor necrosis factor inhibitors. Retention, remission, LDA, and response rates were significantly better for b/tsDMARD-naive patients, were independent of time since diagnosis, and varied significantly across the European countries.

Objective: To describe baseline characteristics and to compare treatment effectiveness of secukinumab versus tumor necrosis factor inhibitors (TNFi) in patients with spondyloarthritis (SpA) using adalimumab as the main comparator. Methods: This was an observational, prospective cohort study. Patients with SpA (clinical ankylosing spondylitis, nonradiographic axial SpA, or undifferentiated SpA) starting secukinumab or a TNFi during 2015–2018 were identified from 5 Nordic clinical rheumatology registries. Data on comorbidities and extraarticular manifestations (psoriasis, uveitis, and inflammatory bowel disease) were captured from national registries (data available in 94% of patients) and included in multivariable analyses. We assessed 1-year treatment retention (crude survival curves, adjusted hazard ratios [HRadj] for treatment discontinuation) and 6-month response rates (Ankylosing Spondylitis Disease Activity Score [ASDAS] score adj 1.43 [95% CI 1.12–1.81]). Across treatment lines, secukinumab had poorer estimates for 6-month response rates than adalimumab, statistically significantly only for the third-plus line (adjusted analyses: ASDAS score

High-density lipoprotein (HDL) is well-known for its cardioprotective effects, as it possesses anti-inflammatory, anti-oxidative, anti-thrombotic, and cytoprotective properties. Traditionally, studies and therapeutic approaches have focused on raising HDL cholesterol levels. Recently, it became evident that, not HDL cholesterol, but HDL composition and functionality, is probably a more fruitful target. In disorders, such as chronic kidney disease or cardiovascular diseases, it has been observed that HDL is modified and becomes dysfunctional. There are different modification that can occur, such as serum amyloid, an enrichment and oxidation, carbamylation, and glycation of key proteins. Additionally, the composition of HDL can be affected by changes to enzymes such as cholesterol ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), and phospholipid transfer protein (PLTP) or by modification to other important components. This review will highlight some main modifications to HDL and discuss whether these modifications are purely a consequential result of pathology or are actually involved in the pathology itself and have a causal role. Therefore, HDL composition may present a molecular target for the amelioration of certain diseases, but more information is needed to determine to what extent HDL modifications play a causal role in disease development.

Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatic disease. It represents a group of heterogenous inflammatory disorders with unknown origin and is a diagnosis of exclusion in which imaging plays an important role. JIA is defined as arthritis of one or more joints that begins before the age of 16 years, persists for more than 6 weeks and is of unknown aetiology and pathophysiology. The clinical goal is early suppression of inflammation to prevent irreversible joint damage which has shifted the emphasis from detecting established joint damage to proactively detecting inflammatory change. This drives the need for imaging techniques that are more sensitive than conventional radiography in the evaluation of inflammatory processes as well as early osteochondral change. Physical examination has limited reliability, even if performed by an experienced clinician, emphasising the importance of imaging to aid in clinical decision-making. On behalf of the European Society of Musculoskeletal Radiology (ESSR) arthritis subcommittee and the European Society of Paediatric Radiology (ESPR) musculoskeletal imaging taskforce, based on literature review and/or expert opinion, we discuss paediatric-specific imaging characteristics of the most commonly involved, in literature best documented and clinically important joints in JIA, namely the temporomandibular joints (TMJs), spine, sacroiliac (SI) joints, wrists, hips and knees, followed by a clinically applicable point to consider for each joint. We will also touch upon controversies in the current literature that remain to be resolved with ongoing research. Key Points: • Juvenile idiopathic arthritis (JIA) is the most common chronic paediatric rheumatic disease and, in JIA imaging, is increasingly important to aid in clinical decision-making. • Conventional radiographs have a lower sensitivity and specificity for detection of disease activity and early destructive change, as compared to MRI or ultrasound. Nonetheless, radiography remains important, particularly in narrowing the differential diagnosis and evaluating growth disturbances. • Mainly in peripheral joints, ultrasound can be helpful for assessment of inflammation and guiding joint injections. In JIA, MRI is the most validated technique. MRI should be considered as the modality of choice to assess the axial skeleton or where the clinical presentation overlaps with JIA., SCOPUS: re.j, info:eu-repo/semantics/published

ObjectiveTo update the European League Against Rheumatism (EULAR) recommendations for the pharmacological treatment of psoriatic arthritis (PsA).MethodsAccording to the EULAR standardised operating procedures, a systematic literature review was followed by a consensus meeting to develop this update involving 28 international taskforce members in May 2019. Levels of evidence and strengths of recommendations were determined.ResultsThe updated recommendations comprise 6 overarching principles and 12 recommendations. The overarching principles address the nature of PsA and diversity of both musculoskeletal and non-musculoskeletal manifestations; the need for collaborative management and shared decision-making is highlighted. The recommendations provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs and local glucocorticoid injections are proposed as initial therapy; for patients with arthritis and poor prognostic factors, such as polyarthritis or monoarthritis/oligoarthritis accompanied by factors such as dactylitis or joint damage, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drugs (bDMARDs) targeting tumour necrosis factor (TNF), interleukin (IL)-17A or IL-12/23 should be initiated, taking into account skin involvement if relevant. If axial disease predominates, a TNF inhibitor or IL-17A inhibitor should be started as first-line disease-modifying antirheumatic drug. Use of Janus kinase inhibitors is addressed primarily after bDMARD failure. Phosphodiesterase-4 inhibition is proposed for patients in whom these other drugs are inappropriate, generally in the context of mild disease. Drug switches and tapering in sustained remission are addressed.ConclusionThese recommendations provide stakeholders with an updated consensus on the pharmacological management of PsA, based on a combination of evidence and expert opinion.

This study examined the criterion validity of self-reported running-related injuries (RRI) by novice runners. Fifty-eight participants (41 females; age 46 ± 11 yrs) of the "Start-to-Run" program provided self-reports on their RRIs using an online questionnaire. Subsequently, they attended injury consultations with sports medicine physicians who provided physician-reports (blinded for the self-reports) as a reference standard. Self-reports and physician-reports included information on injury location (i.e., hip/groin, upper leg, knee, lower leg, and ankle/foot) and injury type (i.e., muscle-tendon unit, joint, ligament, or bone). Sensitivity, specificity, and positive predictive values were 100% for all five injury locations. For injury type, sensitivity was low (66% for muscle-tendon unit, 50% for ligament, and 40% for bone) and lowest for joint injuries (17%). In conclusion, the validity of self-reported RRIs by novice runners is good for injury locations but not for injury types. In particular for joint injuries, the validity of novice runners' self-reports is low.ABBREVIATIONS: RRI: Running Related Injury; SMC: Sports Medicine Centre; MTU: Muscle Tendon Unit; PPV: Positive Predictive Value.

Psoriatic arthritis (PsA) is a chronic, inflammatory disease. The effects of PsA real-world treatment patterns on patient-reported outcomes in the US and 5 European countries (EU5; France, Germany, Italy, Spain, UK) were evaluated. Respondents from the 2016 National Health and Wellness Survey received advanced therapies (e.g., biologic disease-modifying antirheumatic drugs [DMARDs]), other therapies, (e.g., conventional synthetic DMARDs), or no treatment. Assessments included demographics, disease severity (patient-reported), comorbidities (Charlson Comorbidity Index), health status (Short Form-36 Health Survey), depression (Patient Health Questionnaire-9), work productivity (Work Productivity and Activity Index), and treatment adherence (Morisky Medication Adherence Scale-8). Overall, 1037 respondents from the US and 947 respondents from the EU5 were included. Of these, 21.7% US and 7.3% EU5 respondents received advanced therapies; 16.6% and 28.5%, other therapies; and 61.7% and 64.2%, no treatment, respectively. During treatment with advanced or other therapies, 40.8–54.7% US and 57.7–58.9% EU5 respondents self-reported moderate or severe PsA. Respondents receiving advanced therapies had the highest Charlson Comorbidity Index score (US, 1.25; EU5, 1.42); the lowest scores were with no treatment (0.52 and 0.49, respectively). Employment was lowest with other therapies (US, 47.7%; EU5, 41.1%). Overall work impairment was reported by 57.9% US and 62.6% EU5 respondents receiving advanced therapies. Medication adherence was generally low in the US and medium in the EU5 (Morisky Medication Adherence Scale-8: low, US 40.1–46.7%, EU5, 29.0–35.2%; medium, US 29.3–36.1%, EU5 37.8–49.3%; high, US 23.8–24.0%; EU5, 21.7–27.0%). Advanced and other therapies reduced PsA severity; however, > 40% of respondents reported moderate or severe PsA during treatment. Better management and adherence may reduce unmet need and disease burden. Further work is required to improve PsA diagnosis and time to treatment initiation. Electronic supplementary material The online version of this article (10.1007/s00296-018-4195-x) contains supplementary material, which is available to authorized users.

Biologic therapies have changed the outcome of both adult and pediatric patients with Inflammatory Bowel Disease (IBD). In September 2013, the first biosimilar of infliximab was introduced into the pharmaceutical market. In 2015, a first position paper on the use of biosimilars in pediatric IBD was published by the ESPGHAN IBD Porto group. Since then, more data have accumulated for both adults and children demonstrating biosimilars are an effective and safe alternative to the originator. In this updated position statement, we summarize current evidence and provide joint consensus statements regarding the recommended practice of biosimilar use in children with IBD. ispartof: JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION vol:68 issue:1 pages:144-153 ispartof: location:United States status: published

The most prevalent health concerns in patients with axial spondyloarthritis (axSpA) include spinal stiffness, spinal pain, mobility limitations, fatigue, and disturbed sleep. Many patients experience impairments related to extraspinal disease, extra-articular disease, or drug side effects. To capture overall life impact, self-reported measurement instruments assessing health-related quality of life (HRQoL) have been developed. This article summarizes the literature on relevant concepts and frameworks when measuring overall health or HRQoL, available measures assessing this outcome in axSpA, the hierarchical relations between overall health/ HRQoL and specific axSpA impairments, and the role of context when interpreting interventions for overall health or HRQoL outcomes.

HMG-CoA reductase inhibitors, or statins, are potent plasma LDL-cholesterol (LDL-c) lowering agents. Since the introduction of the first statin, lovastatin, in 1987, accumulating evidence showed that non-cholesterol lowering effects play an important role in their efficacy to reduce atherosclerotic cardiovascular disease (ASCVD). Thus, these non-LDL-c lowering properties could benefit patients with immune-mediated diseases. Statins and their associated immune-modulating roles have recently received much attention. Different statins have been administered in various experimental and clinical studies focused on autoimmunity. The results indicate that statins can modulate immune responses through mevalonate pathway-dependent and-independent mechanisms. The antiinflammatory and immune-modulating effects include cell adhesion, migration of antigen presenting cells, and differentiation, as well as activation, of T-cells. In various autoimmune diseases (e.g. rheumatoid arthritis, lupus, and multiple sclerosis), promising results have been obtained to date. (C) 2020 Elsevier Inc. All rights reserved.

The aim of this study is to investigate whether methotrexate-induced nausea is associated with anxiety or the use of coping strategies in children with juvenile idiopathic arthritis (JIA) treated with methotrexate (MTX). This is an observational study of children diagnosed with JIA (ILAR criteria), treated with MTX and aged 9 years or above. MTX-induced nausea was determined by the children’s completion of a nausea diary and the parents’ completion of the Methotrexate Intolerance Severity Score (MISS). Anxiety was assessed by the Beck Youth Inventories-Anxiety Inventory (BYI-A) and coping strategies were evaluated by an adapted Nausea Coping Questionnaire. Enrolled were 121 children (82 girls: 39 boys) with a median age (IQR) of 13.3 (11.3–15.1) years. The median MTX-dose (IQR) was 9.7 (9.0–10.9) mg/m2/week. The median treatment duration (IQR) was 340 (142–766) days. The MISS was completed for 120 children; 77 children completed the nausea diary for at least 7 days. MTX-induced nausea was present in 61% (73/120) of the children according to the MISS and in 73% (56/77) of the children according to the nausea diary. MTX-induced nausea was associated with a more frequent use of the coping strategy internalizing/catastrophizing (MISS, p = 0.012; diary, p < 0.0001) and higher BYI-A raw scores (diary, p = 0.016). MTX-induced nausea was associated with anxiety and the use of coping strategies in children with JIA. These psychological factors may be part of the mechanism behind the inter-individual variation in the level of nausea to MTX treatment.

Objective: To identify novel genetic and epigenetic factors associated with Myasthenia gravis (MG) using an identical twins experimental study design.Methods: The transcriptome and methylome of peripheral monocytes were compared between mono zygotic (MZ) twins discordant and concordant for MG, as well as with MG singletons and healthy controls, all females. Sets of differentially expressed genes and differentially methylated CpGs were validated using RT-PCR for expression and target bisulfite sequencing for methylation on additional samples.Results: >100 differentially expressed genes and similar to 1800 differentially methylated CpGs were detected in peripheral monocytes between MG patients and controls. Several transcripts associated with immune homeostasis and inflammation resolution were reduced in MG patients. Only a relatively few genes differed between the discordant healthy and MG co-twins, and both their expression and methylation profiles demonstrated very high similarity.Interpretation: This is the first study to characterize the DNA methylation profile in MG, and the expression profile of immune cells in MZ twins with MG. Results suggest that numerous small changes in gene expression or methylation might together contribute to disease. Impaired monocyte function in MG and decreased expression of genes associated with inflammation resolution could contribute to the chronicity of the disease. Findings may serve as potential new predictive biomarkers for disease and disease activity, as well as potential future targets for therapy development. The high similarity between the healthy and the MG discordant twins, suggests that a molecular signature might precede a clinical phenotype, and that genetic predisposition may have a stronger contribution to. disease than previously assumed. (C) 2017 Elsevier Ltd. All rights reserved.

Dietary patterns may play an important role in musculoskeletal well-being. However, the link between dietary patterns, the components of patients’ diet, and chronic musculoskeletal pain remains unclear. Therefore, the purpose of this review was to systematically review the literature on the link between dietary patterns, the components of patients’ diet and chronic musculoskeletal pain. This review was conducted following the “Preferred Reporting Items for Systematic reviews and Meta-Analyses” (PRISMA) guidelines and was registered in PROSPERO with the registration number CRD42018110782. PubMed, Web of Science, and Embase online databases were searched. After screening titles and abstracts of 20,316 articles and full texts of 347 articles, 12 eligible articles were included in this review, consisting of nine experimental and three observational studies. Seven out of nine experimental studies reported a pain-relieving effect of dietary changes. Additionally, protein, fat, and sugar intake were found to be associated with pain intensity and pain threshold. In conclusion, plant-based diets might have pain relieving effects on chronic musculoskeletal pain. Patients with chronic rheumatoid arthritis pain can show inadequate intake of calcium, folate, zinc, magnesium, and vitamin B6, whilst patients with fibromyalgia can show a lower intake of carbohydrates, proteins, lipids, vitamin A-E-K, folate, selenium, and zinc. Chronic pain severity also shows a positive relation with fat and sugar intake in osteoarthritis, and pain threshold shows a positive association with protein intake in fibromyalgia.