A direct comparison in diagnostic performance of CDUS, FDG-PET/CT and MRI in patients suspected of giant cell arteritis.

OBJECTIVES: This study directly compares diagnostic performance of Colour Duplex Ultrasound (CDUS), Fluor-18-deoxyglucose Positron Emission Tomography Computed Tomography (FDG-PET/CT) and Magnetic Resonance Imaging (MRI) in patients suspected of giant cell arteritis (GCA). METHODS: Patients with suspected GCA were included in a nested-case control pilot study. CDUS, whole body FDG-PET/CT and cranial MRI were performed within 5 working days after initial clinical evaluation. Clinical diagnosis after six months follow-up by experienced rheumatologists in the field of GCA, blinded for imaging, was used as reference standard. Diagnostic performance of the imaging modalities was determined. Stratification for GCA subtype was performed and imaging results were evaluated in different risk stratification groups. RESULTS: In total, 23 patients with GCA and 19 patients suspected of but not diagnosed with GCA were included. Sensitivity was 69.6% (95%CI 50.4%-88.8%) for CDUS, 52.2% (95%CI 31.4%-73.0%) for FDG-PET/CT and 56.5% (95%CI 35.8%-77.2%) for MRI. Specificity was 100% for CDUS, FDG-PET/CT and MRI. FDG-PET/CT was negative for GCA in all isolated cranial GCA patients (n = 8), while MRI was negative in all isolated extracranial GCA patients (n = 4). In 4 GCA patients with false-negative (n = 2; intermediate and high risk) or inconclusive (n = 2; low and intermediate risk) CDUS results, further imaging confirmed diagnosis. CONCLUSIONS: Sensitivity of CDUS was highest, while specificity was excellent in all imaging modalities. Nevertheless, confidence intervals of all imaging modalities were overlapping. Following EULAR recommendations, CDUS can be used as a first test to diagnose GCA. With insufficient evidence for GCA, further testing considering GCA subtype is warranted.

External validation of the giant cell arteritis probability score in the Netherlands.

OBJECTIVES: To prevent complications of giant cell arteritis (GCA), early and accurate diagnosis is essential. Recently, Laskou et al. (2019) developed the giant cell arteritis probability score (GCAPS) which allows physicians to assess the likelihood of GCA at an early stage. The aim of this study was to validate the GCAPS in a Dutch hospital. METHODS: A retrospective cohort of patients with suspected GCA between January 1st, 2017 and October 1st, 2019 was used. As the variable extracranial artery abnormality was not measured, a modified GCAPS was used (m-GCAPS). Clinical diagnosis of the rheumatologist after six months follow-up was used as reference. The m-GCAPS was assessed for discrimination and calibration. We applied risk stratification according to Sebastian et al. (2020) (low, intermediate and high-risk groups based on the median and 75th percentile). RESULTS: Our study included 209 suspected GCA patients. 135 patients had complete records. Of these patients, 40 had GCA. The m-GCAPS had an area under the curve of 0.83, a sensitivity of 80.0% and specificity of 75.8% at the optimal cut-off value >10.5. The Hosmer-Lemeshow test was non-significant. Using risk stratification, GCA prevalence was 12.5% in the low (score<9), 23.3% in the intermediate (9-12) and 78.6% in the high-risk group (>12). CONCLUSIONS: The m-GCAPS showed good discrimination and calibration in a Dutch retrospective cohort and can aid early recognition of GCA. Stratification into low, intermediate and high-risk is promising, but might need optimisation.

Do we need to lower the cut point of the 2010 ACR/EULAR classification criteria for diagnosing rheumatoid arthritis?

OBJECTIVE: In this study we aimed to evaluate the effect of lowering the cut point of the 2010 criteria to identify more patients with RA among early inflammatory arthritis patients. METHODS: We included early arthritis patients from the Rotterdam Early Arthritis Cohort with at least one joint with clinical synovitis and symptoms for <1 year, with no other explanation for their symptoms. The demographic and clinical characteristics of each patient were recorded at baseline. Patients were classified as case or non-case at the 1-year follow-up by the definition used in the development of the 2010 criteria (MTX initiation). To assess the diagnostic performance of the 2010 criteria, the sensitivity and specificity at each cut point were determined. RESULTS: We included 557 patients in our analysis. At the 1-year follow-up, 253 patients (45%) were classified as case (MTX use). In the group of patients who scored 0-5 points (n = 328), 98 patients (30%) were classified as case (MTX use). The sensitivity and specificity of the 2010 criteria using the cut point of 6 were 61% and 76%, respectively. With the cut point of 5, the sensitivity would increase to 76% and the specificity would decrease to 68%. CONCLUSION: By lowering the cut point of the 2010 criteria from 6 to 5 points, we were able to identify 15% more RA patients at the cost of 8% more false-positive patients.

Diagnostic delay in patients with giant cell arteritis: results of a fast-track clinic.

Giant cell arteritis (GCA) can lead to severe complications if left untreated. The aim of this study was to describe time from onset of symptoms to diagnosis and treatment in GCA suspected patients in a fast-track clinic (FTC), and secondarily to assess the influence of GCA symptoms on this time. A retrospective cohort consisting of suspected GCA patients who visited the FTC between January 2017 and October 2019 was used. Time between symptom onset, first general practitioner visit, FTC referral, first FTC visit, and treatment initiation was analysed. Furthermore, this was stratified for subtypes of GCA and GCA symptoms. Of 205 patients referred with suspected GCA, 61 patients received a final diagnosis of GCA (GCA+) and 144 patients had no GCA (GCA-). Median time after onset of symptoms to first FTC visit was 31.0 days (IQR 13.0-108.8) in all referred patients. Time between onset of symptoms and first GP visit was 10.5 (4.0-36.3) days, and time between first GP visit and FTC referral was 10.0 (1.0-47.5) days. Patients were generally seen at the FTC within 1 day after referral. For patients with isolated cranial GCA (n = 41), median delay from onset of symptoms to treatment initiation was 21.0 days (11.0-73.5), while this was 57.0 days (33.0-105.0) in patients with extracranial large-vessel involvement (n = 20) (p = 0.02). Our results indicate considerable delay between symptom onset and FTC referral in patients suspected of GCA. Suspected patients were examined and GCA+ patients were treated instantly after referral. Key Points • GCA can cause severe complications with delayed treatment, but non-specific symptoms make diagnosis challenging. • Diagnostic delay still occurs despite introducing a successful fast-track clinic resulting from delay between start of symptoms and FTC referral. • Patients who presented with constitutional symptoms had longer delay than patients who presented with isolated cranial symptoms.

External validation of the 2022 ACR/EULAR classification criteria in patients with suspected giant cell arteritis in a Dutch fast-track clinic.

OBJECTIVE: Recently 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. METHODS: Patients 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. RESULTS: In 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. CONCLUSION: Our 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.

Comparing Diagnostic Performance of Short and Long [18F]FDG-PET Acquisition Times in Giant Cell Arteritis.

(1) Background: In giant cell arteritis (GCA), the assessment of cranial arteries using [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) combined with low-dose computed tomography (CT) may be challenging due to low image quality. This study aimed to investigate the effect of prolonged acquisition time on the diagnostic performance of [18F]FDG PET/CT in GCA. (2) Methods: Patients with suspected GCA underwent [18F]FDG-PET imaging with a short acquisition time (SAT) and long acquisition time (LAT). Two nuclear medicine physicians (NMPs) reported the presence or absence of GCA according to the overall image impression (gestalt) and total vascular score (TVS) of the cranial arteries. Inter-observer agreement and intra-observer agreement were assessed. (3) Results: In total, 38 patients were included, of whom 20 were diagnosed with GCA and 18 were without it. Sensitivity and specificity for GCA on SAT scans were 80% and 72%, respectively, for the first NMP, and 55% and 89% for the second NMP. On the LAT scans, these values were 65% and 83%, and 75% and 83%, respectively. When using the TVS, LAT scans showed especially increased specificity (94% for both NMPs). Observer agreement was higher on the LAT scans compared with that on the SAT scan. (4) Conclusions: LAT combined with the use of the TVS may decrease the number of false-positive assessments of [18F]FDG PET/CT. Additionally, LAT and TVS may increase both inter and intra-observer agreement.

Diagnostic Performance and Clinical Utility of Referral Rules to Identify Primary Care Patients at Risk of an Inflammatory Rheumatic Disease.

OBJECTIVE: To determine the diagnostic performance and clinical utility of the Rotterdam Early Arthritis Cohort (REACH) and the Clinical Arthritis Rule (CARE) referral rules in an independent population of unselected patients from primary care. METHODS: This study consisted of adults who were suspected of the need for referral to a rheumatologist by their general practitioner. Diagnostic accuracy measures and a net benefit approach were used to compare both rules to usual care for recognizing inflammatory arthritis and inflammatory rheumatic diseases (IRDs). Using the least absolute shrinkage and selection operator method and cross-validation we created an optimal prediction rule for IRD. RESULTS: This study consisted of 250 patients, of whom 42 (17%) were diagnosed with inflammatory arthritis and 55 (22%) with an IRD 3 months after referral. Considering inflammatory arthritis, the area under the receiver operating characteristic curve (AUC) was 0.72 (95% confidence interval [95% CI] 0.64-0.80) for REACH and 0.82 (95% CI 0.75-0.88) for CARE. Considering IRD, the AUC was 0.66 (95% CI 0.58-0.74) for REACH and 0.76 (95% CI 0.69-0.83) for CARE. CARE was of highest clinical value when compared to usual care. The composite referral rule for IRD of 10 parameters included sex, age, joint features, acute onset of symptoms, physical limitations, and duration of symptoms (AUC 0.82 [95% CI 0.75-0.88]). CONCLUSION: Both validated rules have a net benefit in recognizing inflammatory arthritis as well as IRD compared to usual care, but CARE shows superiority over REACH. Although the composite referral rule indicates a greater diagnostic performance, external validation is needed.

Diagnostic performance of the ACR/EULAR 2010 criteria for rheumatoid arthritis and two diagnostic algorithms in an early arthritis clinic (REACH).

INTRODUCTION: An ACR/EULAR task force released new criteria to classify rheumatoid arthritis at an early stage. This study evaluates the diagnostic performance of these criteria and algorithms by van der Helm and Visser in REACH. METHODS: Patients with symptoms ≤12 months from REACH were used. Algorithms were tested on discrimination, calibration and diagnostic accuracy of proposed cut-points. Two patient sets were defined to test robustness; undifferentiated arthritis (UA) (n=231) and all patients including those without synovitis (n=513). The outcomes evaluated were methotrexate use and persistent disease at 12 months. RESULTS: In UA patients all algorithms had good areas under the curve 0.79, 95% CI 0.73 to 0.83 for the ACR/EULAR criteria, 0.80, 95% CI 0.74 to 0.87 for van der Helm and 0.83, 95% CI 0.77 to 0.88 for Visser. All calibrated well. Sensitivity and specificity were 0.74 and 0.66 for the ACR/EULAR criteria, 0.1 and 1.0 for van der Helm and 0.59 and 0.93 for Visser. Similar results were found in all patients indicating robustness. CONCLUSION: The ACR/EULAR 2010 criteria showed good diagnostic properties in an early arthritis cohort reflecting daily practice, as did the van der Helm and Visser algorithms. All were robust. To promote uniformity and comparability the ACR/EULAR 2010 criteria should be used in future diagnostic studies.

Periarticular osteoporosis: a useful feature in the diagnosis of early rheumatoid arthritis? Reliability and validity in a cross-sectional diagnostic study using dual-energy X-ray absorptiometry.

OBJECTIVES: To identify regions of interest (ROIs) relevant to periarticular osteoporosis in RA with low precision error and sufficient inter-rater reliability and to test diagnostic validity for RA. METHODS: Periarticular BMD was measured using dual-energy X-ray absorptiometry (DXA). Five ROIs were defined around MCP and/or PIP joints II-V, II-IV and mid-metacarpal to mid-phalangeal. They were evaluated for precision using the root mean square coefficient of variation (RMS-CV) and the intra-class correlation coefficient (ICC) for inter-reader reliability. To test validity, established RA patients (n = 25) and early arthritis patients (n = 25) were compared with healthy controls (n = 37) matched on sex, age and menopausal status using paired t-tests, ROC curves and scatterplots. RESULTS: The RMS-CV was 0.45-1.07%. The ICC was 0.99. Mean BMDs of the five ROIs ranged from 0.321 to 0.372 g/cm(2) in established RA, from 0.321 to 0.382 g/cm(2) in early arthritis and from 0.342 to 0.401 g/cm(2) in healthy controls. Mean differences ranged from 0.012 to 0.032 g/cm(2) for established RA and from 0.023 to 0.033 g/cm(2) for early arthritis patients compared with matched controls, with P < 0.05 for ROIs 1-5 in early arthritis and the whole hand in established RA. ROC curves indicated low discriminative power, with an area under the curve (AUC) of 0.61-0.64, and scatterplots showed great overlap between BMD values of patients and controls. CONCLUSIONS: Periarticular BMD measured with DXA seems not to be a useful diagnostic feature due to strong overlap of BMD values between healthy controls, established RA patients and early arthritis patients.

A Tale of Diagnostic Delay with Detrimental Consequences: Illustrating the Challenging Nature of Diagnosing Giant Cell Arteritis.

Giant cell arteritis is a medical emergency as severe, irreversible complications may occur if it is not treated in a timely manner. However, in daily practice early diagnosis can be challenging. We report the case of a 70-year-old woman who presented with multiple ischaemic cerebral vascular accidents related to newly diagnosed giant cell arteritis. Review of her charts revealed a substantial delay from the onset of symptoms to diagnosis. This case demonstrates the need for additional efforts to reduce delay in referring patients with giant cell arteritis and the need to implement fast-track clinics to prevent serious complications. LEARNING POINTS: Giant cell arteritis is a medical emergency and unnecessary diagnostic delay can result in severe complications.Despite implementation of fast-track clinics, diagnostic delay still occurs due to the generic nature of signs and symptoms and inadequate case finding.As diagnostic delay can lead to preventable complications, increased knowledge and awareness of the characteristics and urgency of giant cell arteritis is needed among referring physicians.

Painful knees and hearing-loss: a rare presentation of meningococcal disease.

A 49-year-old woman with a medical history of rheumatoid arthritis presented to the emergency room, with high fever and painful knees. In addition, she had had a mild headache for several days and some hearing loss over several months. We saw an ill patient with arthritis of both knees, from which purulent fluid was aspirated. Antibiotics were started for septic arthritis of both knees and her condition improved rapidly. However, the headache persisted and the hearing loss worsened. At the time, meningitis was suspected. Initial knee aspiration culture was positive for Neisseria meningitidis PCR of the cerebrospinal fluid sample also was positive for N. meningitidis The patient was finally diagnosed with bilateral septic gonarthritis secondary to a bacterial meningitis caused by N. meningitidis.

Reappraisal of the diagnostic and prognostic value of morning stiffness in arthralgia and early arthritis: results from the Groningen EARC, Leiden EARC, ESPOIR, Leiden EAC and REACH.

INTRODUCTION: Morning stiffness is assessed daily in the diagnostic process of arthralgia and arthritis, but large-scale studies on the discriminative ability are absent. This study explored the diagnostic value of morning stiffness in 5,202 arthralgia and arthritis patients and the prognostic value in early rheumatoid arthritis (RA). METHODS: In arthralgia patients referred to the Early Arthritis Recognition Clinics (EARC) of Leiden (n = 807) and Groningen (n = 481) or included in the Rotterdam Early Arthritis Cohort (REACH) study (n = 353), the associations (cross-sectional analyses) between morning stiffness and presence of arthritis at physical examination were studied. In early arthritis patients, included in the Leiden Early Arthritis Clinic (EAC) (n = 2,748) and Evaluation et Suivi de POlyarthrites Indifférenciées Récentes (ESPOIR) (n = 813), associations with fulfilling the 2010-RA criteria after one year were assessed. In 2010-RA patients included in the EAC (n = 1,140) and ESPOIR (n = 677), association with the long-term outcomes of disease-modifying antirheumatic drug (DMARD)-free sustained remission and radiological progression were determined. Morning stiffness was defined as a duration ≥60 minutes; sensitivity analyses were performed for other definitions. RESULTS: In arthralgia, morning stiffness (≥60 minutes) associated with the presence of arthritis; Leiden EARC odds ratio (OR) 1.49 (95% CI 1.001 to 2.20), Groningen EARC OR 2.21 (1.33 to 3.69) and REACH OR 1.55 (0.97 to 2.47) but the areas under the receiver operating characteristic curve (AUCs) were low (0.52, 0.57, 0.54). In early arthritis, morning stiffness was associated with 2010-RA independent of other predictors (Leiden EAC OR 1.72 (95% CI 1.31 to 2.25, AUC 0.68), ESPOIR OR 1.68 (1.03 to 2.74, AUC 0.64)). Duration of ≥30 minutes provided optimal discrimination for RA in early arthritis. Morning stiffness was not associated with radiological progression or DMARD-free sustained remission. CONCLUSIONS: Morning stiffness in arthralgia and early arthritis is associated with arthritis and RA respectively. This supports the incorporation of morning stiffness in the diagnostic process.

Quality of life and health care use in patients with arthralgias without synovitis compared with patients diagnosed with early rheumatoid arthritis: data from an early arthritis cohort.

OBJECTIVE: To compare the burden of disease and its development over time in patients referred to an early arthritis cohort who were diagnosed either as having arthralgias without synovitis or as having rheumatoid arthritis (RA). METHODS: Patients diagnosed as having arthralgias without synovitis or RA were selected from the Rotterdam Early Arthritis Cohort. Data on clinical and psychological characteristics, demographics, pain scores (Rheumatoid Arthritis Disease Activity Index), functional ability (Health Assessment Questionnaire), health-related quality of life (HRQOL; Short Form 36), fatigue (visual analog scale and Fatigue Assessment Scale), and health care utilization (HCU) were collected at baseline and at 6 and 12 months of followup. The burden of disease measures (pain, functional ability, fatigue, and HRQOL) and HCU levels were plotted over time for both groups. A Poisson regression model for repeated data was used to identify determinants of HCU for both groups. RESULTS: At baseline, 330 patients with arthralgias without synovitis (nonsynovitis [NS] group) and 244 RA patients (RA group) were included. Overall, the burden of disease measures and HCU levels were very similar between groups. Both groups showed improvement over time with respect to pain scores, functional ability, HRQOL, and HCU levels. Independent predictors of high HCU were identified as more pain, worse physical health, and external locus of control in the NS group and as shorter duration of symptoms, low chance locus of control, and worse physical functioning in the RA group. CONCLUSION: Despite the absence of an inflammatory diagnosis, patients with arthralgias without synovitis experienced a similar burden of disease compared with RA patients.

Selection bias influences reported contralateral breast cancer incidence and survival in high risk non-BRCA1/2 patients.

PURPOSE: The results of studies comparing survival in familial and sporadic breast cancer (BC) are inconsistent. A higher incidence of contralateral breast cancer (CBC) has been reported in familial BC. Ascertainment bias may influence both the reported familial CBC and survival. DESIGN: We assessed CBC incidence, distant disease free (DDFS) and overall survival (OS) in 327 BC patients who had > or =3 breast and/or ovarian cancers in the family but no BRCA1/2 gene mutation (non-BRCA1/2). They were matched to 327 sporadic controls for year and age at detection. To correct for ascertainment bias, we analyzed also separately the results (1) Of the 250 non-BRCA1/2 patients with DNA testing performed before diagnosis or within 2 years ('unselected') and (2) Of the 77 with testing > or =2 years after diagnosis (late-tested). RESULTS: Median follow-up of non-BRCA1/2 patients was 6.1 yrs. Ten years CBC incidence was 11% in non-BRCA1/2 versus 6% in sporadic patients (p = 0.002). At multivariate analysis CBC incidence was increased in late-tested non-BRCA1/2 (HR 4.6; p = 0.001) not in 'unselected' (HR 1.8; p = 0.1). Increased CBC occurred in non-BRCA1/2 patients mainly before genetic testing, suggesting ascertainment bias. Tumors were < or =T1 in 62% of non-BRCA1/2 versus 50% of sporadic patients (p = 0.003), node-negative in 55% versus 52% respectively (p = 0.5). After correction for stage and therapy, OS did not differ between 'unselected' non-BRCA1/2 and sporadic patients (HR 0.8; p = 0.3), but was improved in late-tested non-BRCA1/2. CONCLUSION: Overall survival and contralateral breast cancer incidence were similar in 'unselected' non-BRCA1/2- and sporadic patients. Reports of higher CBC incidence and better survival in non-BRCA1/2 patients may substantially be caused by DNA testing selection-bias.