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Treatment of giant-cell arteritis with tocilizumab, an interleukin-6 receptor alpha inhibitor, while prednisone was tapered over a 26-week period resulted in higher rates of sustained remission than prednisone tapering plus placebo and reduced the total prednisone dose.

To develop evidence-based recommendations for the use of imaging modalities in primary large vessel vasculitis (LVV) including giant cell arteritis (GCA) and Takayasu arteritis (TAK). European League Against Rheumatism (EULAR) standardised operating procedures were followed. A systematic literature review was conducted to retrieve data on the role of imaging modalities including ultrasound, MRI, CT and [18F]-fluorodeoxyglucose positron emission tomography (PET) in LVV. Based on evidence and expert opinion, the task force consisting of 20 physicians, healthcare professionals and patients from 10 EULAR countries developed recommendations, with consensus obtained through voting. The final level of agreement was voted anonymously. A total of 12 recommendations have been formulated. The task force recommends an early imaging test in patients with suspected LVV, with ultrasound and MRI being the first choices in GCA and TAK, respectively. CT or PET may be used alternatively. In case the diagnosis is still in question after clinical examination and imaging, additional investigations including temporal artery biopsy and/or additional imaging are required. In patients with a suspected flare, imaging might help to better assess disease activity. The frequency and choice of imaging modalities for long-term monitoring of structural damage remains an individual decision; close monitoring for aortic aneurysms should be conducted in patients at risk for this complication. All imaging should be performed by a trained specialist using appropriate operational procedures and settings. These are the first EULAR recommendations providing up-to-date guidance for the role of imaging in the diagnosis and monitoring of patients with (suspected) LVV.

BackgroundSince the publication of the European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis (LVV) in 2009, several relevant randomised clinical trials and cohort analyses have been published, which have the potential to change clinical care and therefore supporting the need to update the original recommendations.MethodsUsing EULAR standardised operating procedures for EULAR-endorsed recommendations, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 13 countries. We modified existing recommendations and created new recommendations.ResultsThree overarching principles and 10 recommendations were formulated. We recommend that a suspected diagnosis of LVV should be confirmed by imaging or histology. High dose glucocorticoid therapy (40–60 mg/day prednisone-equivalent) should be initiated immediately for induction of remission in active giant cell arteritis (GCA) or Takayasu arteritis (TAK). We recommend adjunctive therapy in selected patients with GCA (refractory or relapsing disease, presence of an increased risk for glucocorticoid-related adverse events or complications) using tocilizumab. Methotrexate may be used as an alternative. Non-biological glucocorticoid-sparing agents should be given in combination with glucocorticoids in all patients with TAK and biological agents may be used in refractory or relapsing patients. We no longer recommend the routine use of antiplatelet or anticoagulant therapy for treatment of LVV unless it is indicated for other reasons.ConclusionsWe have updated the recommendations for the management of LVV to facilitate the translation of current scientific evidence and expert opinion into better management and improved outcome of patients in clinical practice.

Key Points Giant cell arteritis (GCA) is best understood as an inflammatory vascular syndrome with features of cranial and/or large-vessel vasculitis, systemic inflammation and polymyalgia rheumatica (PMR), which frequently overlap GCA and PMR are among the most common inflammatory rheumatic diseases in the elderly; the prevalence of these diseases is expected to increase due to ageing of the population The role and value of imaging in GCA and PMR is evolving quickly The pathophysiology of GCA is characterized by phases of initiation, transmural inflammation and chronic vessel wall injury and repair, each of which might be novel drug targets Glucocorticoids are the standard-of-care treatment for GCA and PMR, although methotrexate is used in individual cases and anti-IL-6 therapy is now approved for the treatment of GCA The selection of patients for biologic DMARD therapy, defining the best treatment strategies and the development of reliable outcome parameters are challenges in the future management of GCA and PMR Rapid progress in the fields of giant cell arteritis and polymyalgia rheumatica has resulted in the introduction of imaging techniques into routine clinical practice and in promising reports on the efficacy of biologic agents for treatment. Further research should further advance our understanding of the epidemiology, pathogenesis, imaging and treatment of these diseases. The fields of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) have advanced rapidly, resulting in a new understanding of these diseases. Fast-track strategies and improved awareness programmes that prevent irreversible sight loss through early diagnosis and treatment are a notable advance. Ultrasonography and other imaging techniques have been introduced into routine clinical practice and there have been promising reports on the efficacy of biologic agents, particularly IL-6 antagonists such as tocilizumab, in treating these conditions. Along with these developments, which should improve outcomes in patients with GCA and PMR, new questions and unmet needs have emerged; future research should address which pathogenetic mechanisms contribute to the different phases and clinical phenotypes of GCA, what role imaging has in the early diagnosis and monitoring of GCA and PMR, and in which patients and phases of these diseases novel biologic drugs should be used. This article discusses the implications of recent developments in our understanding of GCA and PMR, as well as the unmet needs concerning epidemiology, pathogenesis, imaging and treatment of these diseases.

BackgroundDuring the transition to rheumatoid arthritis (RA) many patients pass through a phase characterised by the presence of symptoms without clinically apparent synovitis. These symptoms are not well-characterised. This taskforce aimed to define the clinical characteristics of patients with arthralgia who are considered at risk for RA by experts based on their clinical experience.MethodsThe taskforce consisted of 18 rheumatologists, 1 methodologist, 2 patients, 3 health professionals and 1 research fellow. The process had three phases. In phase I, a list of parameters considered characteristic for clinically suspect arthralgia (CSA) was derived; the most important parameters were selected by a three-phased Delphi approach. In phase II, the experts evaluated 50 existing patients on paper, classified them as CSA/no-CSA and indicated their level of confidence. A provisional set of parameters was derived. This was studied for validation in phase III, where all rheumatologists collected patients with and without CSA from their outpatient clinics.ResultsThe comprehensive list consisted of 55 parameters, of which 16 were considered most important. A multivariable model based on the data from phase II identified seven relevant parameters: symptom duration <1 year, symptoms of metacarpophalangeal (MCP) joints, morning stiffness duration ≥60 min, most severe symptoms in early morning, first-degree relative with RA, difficulty with making a fist and positive squeeze test of MCP joints. In phase III, the combination of these parameters was accurate in identifying patients with arthralgia who were considered at risk of developing RA (area under the receiver operating characteristic curve 0.92, 95% CI 0.87 to 0.96). Test characteristics for different cut-off points were determined.ConclusionsA set of clinical characteristics for patients with arthralgia who are at risk of progression to RA was established.

Background TNF-α inhibitor (TNFi) serum trough levels have previously been found to be related to disease activity in axial spondyloarthritis (axSpA). However, most research regarding serum trough levels has been conducted in patients who only recently started TNFi therapy. Therefore, our objective was to explore TNFi serum trough level measurements in relation to disease activity and BMI in the total axSpA population in daily clinical practice, also including patients on long-term TNFi therapy. Methods Consecutive patients from the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort were approached for a TNFi serum trough level measurement during their regular outpatient visit at the UMCG. Spearman’s correlation coefficient was used to analyse the relation of serum trough levels with disease activity and BMI. Logistic regression was performed to analyse the relation between therapeutic drug levels and disease activity, corrected for potential confounders, including BMI. Results Thirty-four patients on adalimumab and 21 patients on etanercept were included. Mean age was 45 ± 12 years, 47% were male, median BMI was 26.4 (IQR 23.9–32.5) and median treatment duration was 41 months (range 2–126). According to definitions of Sanquin, 47% of patients had therapeutic serum trough levels. No significant correlations were found between TNFi levels and disease activity (ASDAS-CRP: adalimumab: ρ = -0.16, p  = 0.39; etanercept: ρ = -0.29, p  = 0.20). TNFi levels were moderately correlated with BMI (adalimumab: ρ = -0.48, p  = 0.004; etanercept: ρ = -0.50, p  = 0.021). Patients with active disease (ASDAS ≥ 2.1) showed higher BMI than patients with inactive disease (median 29.7 vs. 24.6, p  = 0.015). In multivariable regression analyses, BMI was identified as the only confounder for the relationship between therapeutic drug levels and ASDAS. Conclusion In this cross-sectional, observational study of axSpA patients mainly on long-term treatment with TNFi, higher BMI was significantly associated with lower adalimumab and etanercept serum trough levels and higher disease activity.

To investigate the influence of patient characteristics on the course of spinal radiographic progression in a large prospective longitudinal cohort study of ankylosing spondylitis (AS) patients treated long-term with TNF-α inhibitors. Consecutive patients from the Groningen Leeuwarden AS (GLAS) cohort starting TNF-α inhibitors with spinal radiographs at least available at baseline and 6 years of follow-up were included. Radiographs were scored using mSASSS by two independent readers. Generalized estimating equations (GEE) were used to explore the associations between baseline characteristics and spinal radiographic progression. The course of radiographic progression in patients with and without risk factors for poor radiographic outcome was investigated using different time models (linear and non-linear). Single linear imputation was used in case of missing radiographic data at the intermediate (2 or 4 years) follow-up visits. 80 AS patients were included with mean baseline mSASSS 8.7±13.3. Baseline syndesmophytes, male gender, older age, longer symptom duration, smoking, and higher BMI were significantly associated with more radiographic damage over time. GEE analysis in patients with these risk factors revealed that radiographic progression followed a non-linear course with mean mSASSS progression rates reducing from max. 2.8 units over 0-2 years to min. 0.9 units over 4-6 years. The GEE model revealed a linear course with overall very low progression (≤1 mSASSS units/2yrs) in patients without risk factors. Complete case analysis in 53 patients showed similar results. AS patients at risk of poor radiographic outcome showed the highest but diminishing spinal radiographic progression during long-term treatment with TNF-α inhibitors.

The pathogenesis of Takayasu arteritis (TAK) is poorly understood and no previous studies have analyzed monocytes in TAK. This study evaluated monocyte subsets and monocyte-related chemokines in the peripheral blood of TAK patients and healthy controls (HC). Monocyte subsets were identified as classical (CD14 + CD16 − ), intermediate (CD14 + CD16 dim ), and non-classical (CD14 dim CD16 high ) in the peripheral blood. The chemokines CCL (C–C chemokine ligand)2, CCL3, CCL4, CCL5, CCL7, CXCL (C-X-C motif ligand)10, and CX3CL (C-X3-C motif ligand)1 were measured in the sera. Thirty-two TAK patients and 30 HC were evaluated. Intermediate monocytes were higher in TAK than HC [25.0 cells ×10 6 /L (16.7–52.0) vs. 17.2 cells ×10 6 /L (9.2–25.3); p  = 0.014]. Active disease was associated with monocytosis ( p  = 0.004 ) , increased classical ( p  = 0.003), and intermediate ( p  < 0.001) subsets than HC. Prednisone reduced the percentage of non-classical monocytes ( p  = 0.011). TAK patients had lower CCL3 ( p  = 0.033) and CCL4 ( p  = 0.023) levels than HC, whereas CCL22 levels were higher in active TAK compared to the remission state ( p  = 0.008). Glucocorticoids were associated with lower CXCL10 levels ( p  = 0.012). In TAK, CCL4 correlated with total (Rho = 0.489; p  = 0.005), classical and intermediate monocytes (Rho = 0.448; p  = 0.010 and Rho = 0.412; p  = 0.019). In conclusion, TAK is associated with altered counts of monocyte subsets in the peripheral blood compared to HC and CCL22 is the chemokine with the strongest association with active disease in TAK.

Bacterial pathogens do not only succeed in breaking the barriers that protect humans from infection, but they also manage to evade insults from the human immune system. The importance of the present study resides in the fact that protein citrullination is shown to represent a new bacterial mechanism for immune evasion. In particular, the oral pathogen P. gingivalis employs this mechanism to defuse innate immune responses by secreting a protein-citrullinating enzyme. Of note, this finding impacts not only the global health problem of periodontitis, but it also extends to the prevalent autoimmune disease rheumatoid arthritis, which has been strongly associated with periodontitis, PPAD activity, and loss of tolerance against citrullinated proteins, such as the histone H3. The keystone oral pathogen Porphyromonas gingivalis is associated with severe periodontitis. Intriguingly, this bacterium is known to secrete large amounts of an enzyme that converts peptidylarginine into citrulline residues. The present study was aimed at identifying possible functions of this citrullinating enzyme, named Porphyromonas peptidylarginine deiminase (PPAD), in the periodontal environment. The results show that PPAD is detectable in the gingiva of patients with periodontitis, and that it literally neutralizes human innate immune defenses at three distinct levels, namely bacterial phagocytosis, capture in neutrophil extracellular traps (NETs), and killing by the lysozyme-derived cationic antimicrobial peptide LP9. As shown by mass spectrometry, exposure of neutrophils to PPAD-proficient bacteria reduces the levels of neutrophil proteins involved in phagocytosis and the bactericidal histone H2. Further, PPAD is shown to citrullinate the histone H3, thereby facilitating the bacterial escape from NETs. Last, PPAD is shown to citrullinate LP9, thereby restricting its antimicrobial activity. The importance of PPAD for immune evasion is corroborated in the infection model Galleria mellonella , which only possesses an innate immune system. Together, the present observations show that PPAD-catalyzed protein citrullination defuses innate immune responses in the oral cavity, and that the citrullinating enzyme of P. gingivalis represents a new type of bacterial immune evasion factor. IMPORTANCE Bacterial pathogens do not only succeed in breaking the barriers that protect humans from infection, but they also manage to evade insults from the human immune system. The importance of the present study resides in the fact that protein citrullination is shown to represent a new bacterial mechanism for immune evasion. In particular, the oral pathogen P. gingivalis employs this mechanism to defuse innate immune responses by secreting a protein-citrullinating enzyme. Of note, this finding impacts not only the global health problem of periodontitis, but it also extends to the prevalent autoimmune disease rheumatoid arthritis, which has been strongly associated with periodontitis, PPAD activity, and loss of tolerance against citrullinated proteins, such as the histone H3.

ObjectiveRecently the Diagnostic and Classification Criteria in Vasculitis Study group developed and published new American College of Rheumatology/EULAR classification criteria for giant cell arteritis (GCA). To test robustness in a different clinical setting and inform clinicians on performance in clinical practice, we aim to externally validate them in patients with a suspicion of GCA referred to our GCA fast-track clinic.MethodsPatients with suspected GCA from the Hospital Group Twente Early GCA in Twente prospective cohort were included. The clinical diagnosis of GCA verified after 6 months of follow-up made by the treating rheumatologist was used as a reference standard. A cut-off score of ≥6 was tested as described in the original article. Area under the receiver operating characteristics curve, sensitivity and specificity were calculated.ResultsIn total, 133 patients with suspected GCA were included, of whom 53 were diagnosed with GCA and 80 patients were not diagnosed with GCA. The area under the curve (AUC) was 0.96 (95% CI 0.92 to 0.98). Using the proposed cut-off score of≥6, we found that sensitivity was 98.0% (95% CI 89.9% to 100%) and specificity was 57.5% (95% CI 45.9% to 68.5%). The majority of misclassified patients without GCA had classification scores of 6 and 7 as clinical and/or laboratory criteria were often present in our non-GCA population.ConclusionOur results showed an excellent AUC and sensitivity with a moderate specificity for classification of GCA patients. Considering our relevant study population, we found that the new classification criteria might also be useful for diagnostic purposes, albeit with careful interpretation.