Blood Biomarkers for Monitoring and Prognosis of Large Vessel Vasculitides.

PURPOSE OF REVIEW: Large vessel vasculitides (LVVs) are inflammatory conditions of the wall of large-sized arteries, mainly represented by giant cell arteritis (GCA) and Takayasu arteritis (TA). The inflammatory process within the vessel wall can lead to serious consequences such as development of aneurysms, strokes and blindness; therefore, early diagnosis and follow-up of LVV are fundamental. However, the arterial wall is poorly accessible and blood biomarkers are intended to help physicians not only in disease diagnosis but also in monitoring and defining the prognosis of these conditions, thus assisting therapeutic decisions and favouring personalised management. The field is the object of intense research as the identification of reliable biomarkers is likely to shed light on the mechanisms of disease progression and arterial remodelling. In this review, we will discuss the role of blood biomarkers in LVVs in the light of the latest evidence. RECENT FINDINGS: In clinical practice, the most widely performed laboratory investigations are the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). However, these indices may be within normal limits during disease relapse and they are not reliable in patients receiving interleukin-6 (IL-6) receptor inhibitors. New biomarkers struggle to gain traction in clinical practice and no molecule with good accuracy has been identified to date. IL-6, a pro-inflammatory cytokine that drives CRP synthesis and increases the ESR, is one of the most promising biomarkers in the field. IL-6 analysis is increasingly performed, and serum levels are more sensitive than ESR for active GCA and might reflect persistent inflammation with high risk of relapse in patients on IL-6 receptor inhibitors. A future with biomarkers that reflect different disease features is an important aspiration. Accordingly, intense effort is being made to identify IL-6-independent inflammatory biomarkers, such as S100 proteins, pentraxin-3 and osteopontin. Moreover, metalloproteinases such as MMP2/9 and angiogenic modulators such as VEGF, YLK-40 and angiopoietins are being studied as markers of arterial remodelling. Lastly, biomarkers indicating organ damage may guide prognostic stratification as well as emergency therapeutic decisions: the most promising biomarkers so far identified are NT-proBNP, which reflects myocardial strain; pentraxin-3, which has been associated with recent optic nerve ischemia; and endothelin-1, which is associated with ischaemic complications. Currently, the use of these molecules in clinical practice is limited because of their restricted availability, lack of sufficient studies supporting their validity and associated costs. Further evidence is required to better interpret their biological and clinical value.

A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis.

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10-54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10-10, OR = 1.28; and rs128738, p = 4.60 × 10-9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis.

A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility.

We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRß1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRß1 13 (p = 4.08 × 10(-43)) and HLA-DQα1 47 (p = 4.02 × 10(-46)), 56, and 76 (both p = 1.84 × 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 × 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.

EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice.

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.

Timing of onset affects arthritis presentation pattern in antisyntethase syndrome.

OBJECTIVES: To evaluate if the timing of appearance with respect to disease onset may influence the arthritis presentation pattern in antisynthetase syndrome (ASSD). METHODS: The patients were selected from a retrospective large international cohort of ASSD patients regularly followed-up in centres referring to AENEAS collaborative group. Patients were eligible if they had an antisynthetase antibody testing positive in at least two determinations along with arthritis occurring either at ASSD onset (Group 1) or during the course of the disease (Group 2). RESULTS: 445 (70%; 334 females, 110 males, 1 transsexual) out of the 636 ASSD we collected had arthritis, in the majority of cases (367, 83%) from disease onset (Group 1). Patients belonging to Group 1 with respect to Group 2 had an arthritis more commonly polyarticular and symmetrical (p=0.015), IgM-Rheumatoid factor positive (p=0.035), erosions at hands and feet plain x-rays (p=0.036) and more commonly satisfying the 1987 revised classification criteria for rheumatoid arthritis (RA) (p=0.004). Features such as Raynaud's phenomenon, mechanic's hands and fever (e.g. accompanying findings) were more frequently reported in Group 2 (p=0.005). CONCLUSIONS: In ASSD, the timing of appearance with respect to disease onset influences arthritis characteristics. In particular, RA features are more common when arthritis occurs from ASSD onset, suggesting an overlap between RA and ASSD in these patients. When arthritis appears during the follow-up, it is very close to a connective tissue disease-related arthritis. Also, the different prevalence of accompanying features between these two groups is in line with this possibility.

Dissecting the inflammatory response in polymyalgia rheumatica: the relative role of IL-6 and its inhibition.

The efficacy of tocilizumab (TCZ), a monoclonal antibody to the interleukin (IL)-6 receptor, in suppressing disease activity in glucocorticoid-naïve patients with new-onset polymyalgia rheumatica (PMR) was studied. Its effect on a panel of cytokines and growth factors was evaluated. Three patients, fulfilling the PMR ACR/EULAR criteria, received TCZ at the dosage of 8 mg/kg every 4 weeks for three times followed by prednisone 0.2 mg/kg in case of inefficacy. Concentrations of IL-10, IL-6, tumour necrosis factor (TNF)-α, IL-1ß, IL-10, IL-17, interferon (IFN)-γ, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and leukaemia inhibitory factor (LIF) were measured at baseline, after 72 h of the first TCZ infusion and then at weeks 1, 4, 5, 8, 9, 12, 13, 14, 16, and 22. A slight clinical improvement was seen only after the first TCZ infusion, but was largely inferior to that of conventional doses of GC administered subsequently. An ischaemic visual accident suggestive of GCA occurred in one patient during TCZ treatment. IL-6 was increased at baseline compared to controls, further increased after the first TCZ infusion, and was suppressed by GC. IL-17 production decreased during TCZ treatment and reverted to pre-treatment levels after GC. VEGF e PDGF showed a less constant pattern, but an increase of VEGF concentration antedated visual symptoms. The other cytokines were not detectable in patients and controls. In our small sample, TCZ was not able to suppress inflammation at the same degree as GC. As a result, monotherapy with TCZ in PMR cannot be recommended, although its efficacy as adjunctive treatment in GC-resistant patients should be further evaluated.

Ankylosis of the wrist bones in patients with rheumatoid arthritis: a study with extremity-dedicated MRI.

OBJECTIVES: Ankylosis, or spontaneous bone fusion, of the small joints of the hand is a rare event in patients with rheumatoid arthritis (RA), being observed in 0.8% of them on conventional radiographs. It is associated with long-lasting and severe disease. In other settings, such as fracture healing, bone fusion is a reparative process. The aim of this paper is the study of the frequency of wrist ankylosis in patients with RA in comparison with other arthritides; to correlate ankylosis with disease activity. METHODS: A total of 94 patients affected by RA, 71 patients with different rheumatic conditions and 42 controls with no joint disease or with slight hand osteoarthritis were studied. DAS-28 CRP was calculated in patients with RA and psoriatic arthritis. MRI of the clinically most involved wrist was performed with a 0.2 T, extremity-dedicated MRI system. RESULTS: Of RA patients, 10/94 (10.6%) showed ankylosis in comparison with 2/113 (1.8%) controls (p=0.015). RA patients with ankylosis had longer disease duration (p=0.019) but similar disease activity. CONCLUSIONS: MRI-defined bone ankylosis is frequent in RA. It is not limited to seronegative spondyloarthritides and may be part of the bone damage observed in RA.

Diagnostic accuracy of ultrasound, conventional radiography and synovial fluid analysis in the diagnosis of calcium pyrophosphate dihydrate crystal deposition disease.

OBJECTIVES: To assess the diagnostic performance of ultrasound (US), x-rays, and microscopic analysis of synovial fluid (SF) for calcium pyrophosphate dihydrate crystal deposition disease (CPPD) using histology as a reference standard. METHODS: We enrolled consecutive patients with osteoarthritis waiting to undergo knee replacement surgery. Each patient underwent US of the knee, focusing on menisci and the hyaline cartilage, the day before surgery. During surgery, SF, menisci and condyles were retrieved and examined microscopically. For the meniscus and cartilage microscopic analysis, 8 samples were collected from each specimen and knee radiographs, performed up to 3 months before surgery, were also assessed. A dichotomous score was given for the presence/absence of CPP for each method. Microscopic findings of the specimens were considered the reference standard. All the procedures followed were in accordance with the ethical standards of the local responsible committee. RESULTS: 42 patients (14 males) were enrolled. All patients underwent US, 34 had eligible radiographs and 32 had SF analysis. 25 patients (59.5%) were positive for CPP at US, 15 (44.1%) at X-ray and 14 (43.7%) at SF. Sensitivity and specificity values were 96% and 87% for US, 75% and 93% for radiography and 77% and 100% for SF respectively. There were no statistically significant differences between the diagnostic performance across single tests. CONCLUSIONS: US proved to be at least as accurate as SF analysis for the diagnosis of CPPD. US, which is feasible and harmless, could be considered the first exam of choice for CPPD diagnosis.

Imaging Techniques in Psoriatic Arthritis: Update 2012-2014 on Current Status and Future Prospects.

By providing additional and more sensitive information over clinical examination, imaging techniques are useful in the assessment of patients with psoriatic arthritis (PsA) and have been increasingly used to obtain additional clues to its pathogenesis. This review describes the current status and future development of conventional radiography, computed tomography, magnetic resonance imaging, positron emission tomography, and other novel techniques in the evaluation of PsA, with a focus on their use in diagnosing, monitoring, and predicting disease course and followup treatment response. The role and applications of ultrasonography are outside the scope and are reviewed elsewhere in these proceedings.

Ultrasound versus low-field magnetic resonance imaging in rheumatic diseases: a systematic literature review.

OBJECTIVES: US and MRI play a significant role in the diagnosis of rheumatic diseases and in monitoring treatment response. This systematic review summarises and evaluates available evidence on the value of low-field MRI compared to US in rheumatic diseases. METHODS: A computerised literature search was conducted by a single reviewer to identify relevant published articles on the diagnostic accuracy of low-field MRI compared to US in rheumatic diseases. The literature search comprised the period from January 1998 to September 2013. RESULTS: The search yielded a total of 1055 articles that were reviewed by title or abstract; finally, 23 articles fulfilling all inclusion criteria were included in the analysis. Our results show that low-field MRI is probably more sensitive than US in the detection of erosions, due to its higher multiplanar capacity. In OA there was a good correlation between US and MRI measurements for cartilage thickness and for effusion in the superior and in the lateral recesses. CONCLUSIONS: There are still few studies comparing US and low-field MRI for their diagnostic and prognostic value in rheumatology and it is currently difficult to draw any firm conclusions on the preferred imaging technique to answer specific clinical questions.

Dynamic contrast-enhanced, extremity-dedicated MRI identifies synovitis changes in the follow-up of rheumatoid arthritis patients treated with rituximab.

OBJECTIVES: The aim of this study is to assess prospectively the effect of rituximab (RTX) on MRI features of wrist joint disease in patients affected by rheumatoid arthritis (RA). METHODS: Ten patients (6F/4M, mean age 52.9±15.5 years) diagnosed with IgM rheumatoid factor, anti-CCP positive, RA according to the 1987 ACR criteria were treated with a single course of RTX (2 infusions of 1000 mg, 15 days apart). MRI of the dominant hand was performed with a 0.2T extremity-dedicated machine using pre and post contrast T1 weighted SE, turbo 3D, and STIR sequences at baseline, and after 4 and 24 weeks. MRI was analysed using the OMERACT-RAMRIS score and the dynamic contrast-enhanced (DCE-MRI) technique for wrist synovitis, which calculates the enhancement ratio as both rate of early enhancement (REE) and relative enhancement (RE). The corresponding ME and IRE parameters were calculated also through a computer-aided semi-automated method on the mean of three MRI slices and on a small ROI positioned in the area of maximum enhancement. RESULTS: DAS significantly decreased during the study period (ANOVA for repeated measures, p=0.005). The RAMRIS score did not change along the study, whereas the dynamic MRI values RE, IRE and ME on the small ROI significantly decreased. RE, but not the RAMRIS synovitis score, significantly correlated with DAS at baseline, 1 and 6 months (p=0.005, 0.04, and 0.0007, respectively). CONCLUSIONS: RTX confirmed good clinical efficacy, which was paralleled by a significant decrease in dynamic MRI results for wrist synovitis. On the contrary, the traditional RAMRIS measures did not change.

Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.

High frequency of capsular knee involvement in polymyalgia rheumatica/giant cell arteritis patients studied by positron emission tomography.

OBJECTIVE: Peripheral arthritis has been described in up to 50% of PMR patients, with knee involvement in the majority. This study was designed to evaluate by PET/CT the knees of patients with PMR and GCA and to identify the knee structures involved by inflammation. METHODS: Twenty-five consecutive patients with PMR (19) or GCA (6) were studied in comparison with 25 age- and sex-matched controls who underwent PET/CT for initial staging of cancer. Clinical features, ESR and CRP were evaluated. Simultaneous FDG-PET and CT imaging from the skull base to the knee was performed after injection of 4.8-5.2 MBq of [(18)F]FDG per kilogram body weight. The knee anatomical structures being evaluated included joints, fibrous capsule, synovial recesses and bursae. RESULTS: At PET/CT, 21/25 patients (84%) showed bilateral diffuse uptake at the knees. The tracer clearly outlined the contour of the fibrous capsule. In 50 knees, 90% of capsular sites were involved by inflammation in comparison with 23% of intracapsular sites and 4.7% of extracapsular sites (P < 0.0001). No correlation was found between PET/CT results and ESR or CRP. FDG uptake, with a pattern similar to that observed in 96% of PMR/GCA patients, was seen in 20% of controls (P = 0.03). CONCLUSION: Our findings suggest that bilateral capsulitis of the knee is detectable in most PMR/GCA patients if a sensitive imaging technique such as PET/CT is used.

Body mass and osteoarthritic pain: results from a study in general practice.

OBJECTIVES: To define the relationship between BMI and pain due to osteoarthritis (OA) of the hand, hip, and knee in patients seen in general practice; to evaluate if overweight is related to co-morbidity and education, and influences the prescription patterns of GPs. METHODS: 2,764 Italian GPs recruited 10 consecutive patients with symptomatic OA, diagnosed according to the ACR criteria. Pain intensity on a visual analogue scale, BMI, years of formal education, comorbidities, pharmacological and non-pharmacological interventions, and referral to specialists were recorded. RESULTS: The most painful joints were the knee in 12,827 patients (53.6%), the hip in 5,645 (23.6%), and the hand in 5,467 (22.8%). A BMI indicative of overweight or obesity was found in 74.8% of men and in 68.3% of women. Mean BMI was higher in knee OA (27.9±3.9), in generalised OA (27.5±4.2), and hip OA (27±3.7) than in hand OA (25.5±3.4). The prevalence of obesity for hip and knee OA was higher than that reported for the general Italian population. Obesity was an important risk factor for pain in all OA localisations. Co-morbidities and lower education were associated with obesity and more intense pain (p<0.0001). Obesity and overweight were less frequent in institutionalised patients. CONCLUSIONS: Our study confirms that more than two thirds of Italian patients with symptomatic OA seen by GPs are overweight or obese. Obesity is clearly associated with OA pain, a finding which is probably underestimated by GPs who are not used to modulate treatment and specialist referral according to patients' BMI.

2012 Provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative.

The objective of this study was to develop European League Against Rheumatism/American College of Rheumatology classification criteria for polymyalgia rheumatica (PMR). Candidate criteria were evaluated in a 6-month prospective cohort study of 125 patients with new-onset PMR and 169 non-PMR comparison subjects with conditions mimicking PMR. A scoring algorithm was developed based on morning stiffness >45 minutes (2 points), hip pain/limited range of motion (1 point), absence of rheumatoid factor and/or anti-citrullinated protein antibody (2 points), and absence of peripheral joint pain (1 point). A score ≥4 had 68% sensitivity and 78% specificity for discriminating all comparison subjects from PMR. The specificity was higher (88%) for discriminating shoulder conditions from PMR and lower (65%) for discriminating RA from PMR. Adding ultrasound, a score ≥5 had increased sensitivity to 66% and specificity to 81%. According to these provisional classification criteria, patients ≥50 years old presenting with bilateral shoulder pain, not better explained by an alternative pathology, can be classified as having PMR in the presence of morning stiffness >45 minutes, elevated C-reactive protein and/or erythrocyte sedimentation rate, and new hip pain. These criteria are not meant for diagnostic purposes.

2012 provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative.

The objective of this study was to develop EULAR/ACR classification criteria for polymyalgia rheumatica (PMR). Candidate criteria were evaluated in a 6-month prospective cohort study of 125 patients with new onset PMR and 169 non-PMR comparison subjects with conditions mimicking PMR. A scoring algorithm was developed based on morning stiffness >45 minutes (2 points), hip pain/limited range of motion (1 point), absence of RF and/or ACPA (2 points), and absence of peripheral joint pain (1 point). A score ≥4 had 68% sensitivity and 78% specificity for discriminating all comparison subjects from PMR. The specificity was higher (88%) for discriminating shoulder conditions from PMR and lower (65%) for discriminating RA from PMR. Adding ultrasound, a score ≥5 had increased sensitivity to 66% and specificity to 81%. According to these provisional classification criteria, patients ≥50 years old presenting with bilateral shoulder pain, not better explained by an alternative pathology, can be classified as having PMR in the presence of morning stiffness>45 minutes, elevated CRP and/or ESR and new hip pain. These criteria are not meant for diagnostic purposes.

Imaging of polymyalgia rheumatica: indications on its pathogenesis, diagnosis and prognosis.

OBJECTIVES: Imaging is one of the most appealing techniques to explore PMR, a disease whose causes, development mechanisms and anatomical targets of inflammatory damage are still scarcely known. This review is concerned with an appraisal of PMR with different imaging modalities with a view to highlighting possible clues to its pathogenesis, diagnosis and prognosis. METHODS: A systematic literature research was performed searching PubMed until July 2010. The Cochrane Library was searched for the relevant reviews, and the abstracts of the ACR and European League Against Rheumatism congresses of the period 2005-10 were reviewed. RESULTS: A total of 1059 papers were retrieved, 46 of which were selected at the end of the review process; 6 of them were concerned with two different imaging techniques. Of these papers, 6 (11.5%) were concerned with conventional radiology; 8 (15.4%) with scintigraphy; 17 (32.7%) with ultrasonography (US); 15 (28.8%) with MRI; and 6 (11.5%) with PET. MRI, US and PET appeared to be the most promising imaging techniques. Bilateral subacromial bursitis, biceps long head tenosynovitis and trochanteric bursitis were particularly consistent findings. In addition, MRI and PET showed interspinous bursitis and PET frequently showed large-vessel vasculitis. Few papers have addressed the role of imaging for diagnosis, differential diagnosis and prognosis of PMR. CONCLUSIONS: Imaging plays an important role in the comprehensive evaluation of PMR, including its pathogenesis, diagnosis and prognosis. Most of its potential is still unexplored, which fact should stimulate further research.

Correlation between computer-aided dynamic gadolinium-enhanced MRI assessment of inflammation and semi-quantitative synovitis and bone marrow oedema scores of the wrist in patients with rheumatoid arthritis--a cohort study.

OBJECTIVE: To test the correlation between assessment of inflammation using dynamic contrast-enhanced MRI (DCE-MRI) analysed by a novel computer-aided approach and semi-quantitative scores of synovitis and bone marrow oedema (BME) using the OMERACT-RA MRI Scoring (RAMRIS) system, in the wrist of patients with RA. METHODS: Fifty-four RA patients had conventional and DCE-MRI of a symptomatic wrist using a low-field 0.2T extremity scanner. RAMRIS synovitis and BME of the wrist joint were done. DCE-MRI data were analysed in three ways: (i) in all images (fully automated approach), (ii) within a large extended region of interest (ROI) placed around the wrist joint (semi-automated approach) and (iii) within a small ROI placed in the area with most visual enhancement (semi-automated approach). Time spent on each procedure was noted. Spearman's rank correlation test was applied to assess the correlation between RAMRIS and the computer-generated dynamic parameters. RESULTS: RAMRIS synovitis (range 2-9), BME (range 0-39) and the dynamic parameters reflecting the number of enhancing voxels were significantly correlated, especially when an extended ROI around the wrist was used (ρ = 0.74; P < 0.01 for synovitis and ρ = 0.82; P < 0.01 for BME). The observer spent on average 20 min (range 12-25 min) to perform RAMRIS, including acquisition of the results in the database, and 8 min (range 7-10 min) to perform all above-mentioned computer-aided analyses. CONCLUSION: Computer-aided analysis of DCE-MRI data correlated with RAMRIS synovitis and BME and was twice as fast to perform. This technique may be useful for quick semi-automated assessment of joint inflammation, but needs further validation.

Subclinical giant cell arteritis in new onset polymyalgia rheumatica A systematic review and meta-analysis of individual patient data.

OBJECTIVES: To determine the prevalence and predictors of subclinical giant cell arteritis (GCA) in patients with newly diagnosed polymyalgia rheumatica (PMR). METHODS: PubMed, Embase, and Web of Science Core Collection were systematically searched (date of last search July 14, 2021) for any published information on any consecutively recruited cohort reporting the prevalence of GCA in steroid-naïve patients with PMR without cranial or ischemic symptoms. We combined prevalences across populations in a random-effect meta-analysis. Potential predictors of subclinical GCA were identified by mixed-effect logistic regression using individual patient data (IPD) from cohorts screened with PET/(CT). RESULTS: We included 13 cohorts with 566 patients from studies published between 1965 to 2020. Subclinical GCA was diagnosed by temporal artery biopsy in three studies, ultrasound in three studies, and PET/(CT) in seven studies. The pooled prevalence of subclinical GCA across all studies was 23% (95% CI 14%-36%, I2=84%) for any screening method and 29% in the studies using PET/(CT) (95% CI 13%-53%, I2=85%) (n=266 patients). For seven cohorts we obtained IPD for 243 patients screened with PET/(CT). Inflammatory back pain (OR 2.73, 1.32-5.64), absence of lower limb pain (OR 2.35, 1.05-5.26), female sex (OR 2.31, 1.17-4.58), temperature >37° (OR 1.83, 0.90-3.71), weight loss (OR 1.83, 0.96-3.51), thrombocyte count (OR 1.51, 1.05-2.18), and haemoglobin level (OR 0.80, 0.64-1.00) were most strongly associated with subclinical GCA in the univariable analysis but not C-reactive protein (OR 1.00, 1.00-1.01) or erythrocyte sedimentation rate (OR 1.01, 1.00-1.02). A prediction model calculated from these variables had an area under the curve of 0.66 (95% CI 0.55-0.75). CONCLUSION: More than a quarter of patients with PMR may have subclinical GCA. The prediction model from the most extensive IPD set has only modest diagnostic accuracy. Hence, a paradigm shift in the assessment of PMR patients in favour of implementing imaging studies should be discussed.