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Peter Engholm Hjort,1,2,* Philip Therkildsen,1,2,* Berit Dalsgaard Nielsen,1– 3 Ib Tønder Hansen,1,2 Mette Nørgaard,2,4 Annette de Thurah,1,2 Ellen-Margrethe Hauge1,2 1Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3Diagnostic Centre, Silkeborg Regional Hospital, Silkeborg, Denmark; 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark*These authors contributed equally to this workCorrespondence: Philip TherkildsenDepartment of Rheumatology, Aarhus University Hospital, Aarhus, DenmarkEmail philther@rm.dkPurpose: To investigate the positive predictive value (PPV) of the giant cell arteritis (GCA) diagnosis in the Danish National Patient Registry (DNPR).Patients and Methods: A total of 293 patients aged ≥ 50 years with a first-time diagnosis of GCA in the DNPR between January 2012 and December 2017 were included. Patients were sampled from two secondary and one tertiary care hospitals in the Central Region Denmark. Two independent investigators (PH & PT) reviewed all medical files, including medical records, treatment, biochemistry, histopathology and imaging, and either confirmed or dismissed the diagnosis of GCA. In case of disagreement, a consensus agreement was reached. Sub-analyses including number of redeemed prescriptions performed temporal artery biopsies (TABs), and number of GCA-related hospital contacts were performed.Results: We confirmed the diagnosis of GCA in 183/293 patients resulting in a PPV of 62% (95% CI: 57– 68). In patients with ≥ 3 redeemed prescriptions of glucocorticoids (GCs), we confirmed the diagnosis in 166/214 resulting in a PPV of 78% (95% CI: 71– 83). In patients with ≥ 3 redeemed prescriptions of GCs and ≥ 3 GCA-related hospital contacts, we confirmed the diagnosis in 88/95 resulting in a PPV of 93% (95% CI: 85– 96); however, this only included 88/183 confirmed GCA patients.Conclusion: This is the first study to validate the diagnostic code of GCA in the DNPR. The overall PPV of GCA in the DNPR was 62%. Requiring redeemed prescriptions of GCs and/or GCA-related hospital contacts increase the PPV, but also excludes a significant number of GCA patients.Keywords: rheumatology, giant cell arteritis, validation, positive predictive value, Danish National Patient Registry

Objective: Intestinal inflammation is frequent in patients with spondyloarthritis (SpA). Here, we test the validity of faecal calprotectin as a marker of intestinal inflammation in SpA patients and evaluate the response of adalimumab in patients with and without intestinal lesions.Method: Patients were included on the basis of active SpA with a Bath Ankylosing Spondylitis Disease Activity Index ≥ 4. After a 4 week non-steroidal anti-inflammatory drug washout period, patients were divided into two groups based on faecal calprotectin level (> 100 mg/kg, n = 15, and < 50 mg/kg, n = 15). Adalimumab 40 mg every other week was initiated. Patients with calprotectin >100 mg/kg received an additional 40 mg of adalimumab at baseline. Patients were followed with clinical examination at weeks 12, 20, and 52; magnetic resonance imaging (MRI) at weeks 0, 20, and 52; and endoscopy at weeks 0 and 20.Results: The groups were similar with regard to clinical disease activity measures at baseline. Faecal calprotectin above 100 mg/kg accurately identified patients with intestinal inflammation. Twelve of the 15 patients with elevated calprotectin had bowel lesions, compared to only one patient in the control group. On MRI, the group with elevated calprotectin had more inflammation in the sacroiliac joints. Finally, the group with intestinal inflammation had a better clinical response to adalimumab, as evaluated by the Ankylosing Spondylitis Disease Activity Score.Conclusion: Elevated faecal calprotectin accurately identified SpA patients with bowel inflammation and more inflammation on MRI. Elevated faecal calprotectin at baseline may predict a better treatment response. [ABSTRACT FROM AUTHOR]

Objectives: To investigate whether a treat-to-target strategy based on methotrexate (MTX) and intra-articular (IA) betamethasone suppresses magnetic resonance imaging (MRI)-determined measures of disease activity and reduces joint destruction in early rheumatoid arthritis (eRA) patients, and to investigate whether concomitant cyclosporin A (CyA) provides an additional effect.Method: In the 2-year randomized, double-blind, treat-to-target trial CIMESTRA, 160 patients with eRA (< 6 months) were randomized to MTX, intra-articular betamethasone and CyA, or placebo CyA. A total of 129 patients participated in the MRI substudy, and had contrast-enhanced MR images of the non-dominant hand at months 0, 6, 12, and 24. MR images were evaluated for osteitis, synovitis, tenosynovitis, bone erosion, and joint space narrowing (JSN), using validated scoring methods.Results: Significant reductions were seen at 6 months in all inflammatory parameters [synovitis, mean change -1.6 (p < 0.001, Wilcoxon), tenosynovitis, -3.5 (p < 0.001), and osteitis, -1.3 (p < 0.05)] and at 12/24 months in synovitis and tenosynovitis [-1.6/-2.2 and -3.6/-3.8, respectively; all p < 0.001]. MRI signs of inflammation were not fully eliminated, and increases in erosion and JSN scores were observed at 6 months [0.4 (p < 0.01)/0.1 (p < 0.05)], 12 months [0.8 (p < 0.001)/0.3 (p < 0.01)], and 24 months [1.0 (p < 0.001)/0.4 (p < 0.001)]. Clinical measures decreased significantly (p < 0.001) at all time points. There were no consistent statistically significant differences between treatment groups.Conclusions: In this eRA treat-to-target trial, MTX and intra-articular glucocorticoids markedly reduced, but did not eliminate, MRI osteitis, synovitis, and tenosynovitis. Accordingly, minimal but statistically significant increases in bone erosion and JSN were observed. No additional effect of CyA was demonstrated. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare tumor necrosis factor alpha inhibitors directly regarding the rates of treatment response, remission, and the drug survival rate in patients with rheumatoid arthritis (RA), and to identify clinical prognostic factors for response. METHODS: The nationwide DANBIO registry collects data on rheumatology patients receiving routine care. For the present study, we included patients from DANBIO who had RA (n = 2,326) in whom the first biologic treatment was initiated (29% received adalimumab, 22% received etanercept, and 49% received infliximab). Baseline predictors of treatment response were identified. The odds ratios (ORs) for clinical responses and remission and hazard ratios (HRs) for drug withdrawal were calculated, corrected for age, disease duration, the Disease Activity Score in 28 joints (DAS28), seropositivity, concomitant methotrexate and prednisolone, number of previous disease-modifying drugs, center, and functional status (Health Assessment Questionnaire score). RESULTS: Seventy percent improvement according to the American College of Rheumatology criteria (an ACR70 response) was achieved in 19% of patients after 6 months. Older age, concomitant prednisolone treatment, and low functional status at baseline were negative predictors. The ORs (95% confidence intervals [95% CIs]) for an ACR70 response were 2.05 (95% CI 1.52-2.76) for adalimumab versus infliximab, 1.78 (95% CI 1.28-2.50) for etanercept versus infliximab, and 1.15 (95% CI 0.82-1.60) for adalimumab versus etanercept. Similar predictors and ORs were observed for a good response according to the European League Against Rheumatism criteria, DAS28 remission, and Clinical Disease Activity Index remission. At 48 months, the HRs for drug withdrawal were 1.98 for infliximab versus etanercept (95% 1.63-2.40), 1.35 for infliximab versus adalimumab (95% CI 1.15-1.58), and 1.47 for adalimumab versus etanercept (95% CI 1.20-1.80). CONCLUSION: Older age, low functional status, and concomitant prednisolone treatment were negative predictors of a clinical response and remission. Infliximab had the lowest rates of treatment response, disease remission, and drug adherence, adalimumab had the highest rates of treatment response and disease remission, and etanercept had the longest drug survival rates. These findings were consistent after correction for confounders and sensitivity analyses and across outcome measures and followup times. [ABSTRACT FROM AUTHOR]

Objective: The objective was to investigate the incidence of late-onset giant cell arteritis (GCA) within the first year in patients diagnosed with polymyalgia rheumatica (PMR)., Methods: In this prospective study, treatment-naïve individuals with a new clinical diagnosis of PMR and without GCA symptoms underwent baseline assessments, including vascular ultrasonography and 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography computed tomography (FDG-PET/CT). To prevent biased inclusion, rapid referral clinics were established for all patients suspected of PMR. Additionally, the patients underwent GCA monitoring during clinical visits at weeks 8 and 10, which involved vascular ultrasonography and FDG-PET/CT scans. After one year, a follow-up visit was performed to confirm the PMR diagnosis and perform vascular ultrasonography., Results: A final PMR diagnosis was assigned to 62 patients, excluding 2 patients with concurrent subclinical GCA and PMR at baseline, corresponding to a baseline prevalence of subclinical GCA of 3%. During the one-year follow-up, two PMR patients developed late-onset GCA corresponding to an incidence rate of 32 per 1000 person-years. One patient developed GCA 14 weeks after the PMR diagnosis, exhibiting cranial symptoms and positive vascular ultrasonography. The other patient presented with subclinical large vessel GCA at the one-year visit detected with vascular ultrasonography and confirmed by FDG-PET/CT., Conclusion: This study is the first to demonstrate a low incidence rate of late-onset GCA in PMR patients within the first year, employing repeated imaging to exclude GCA at baseline and diagnose GCA during follow-up. Additionally, it provides evidence of a low prevalence of subclinical GCA across the entire PMR population., Trial Registration: ClinicalTrials.Gov, NCT04519580., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: In routine care, clinicians may employ 2-[18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) computed tomography (CT) to validate their initial clinical diagnosis of polymyalgia rheumatica (PMR). Nevertheless, the diagnostic utility of combining FDG-PET/CT findings with clinical presentation has not been explored. Therefore, this study aimed to investigate whether the diagnostic accuracy for PMR could be enhanced by combining FDG-PET/CT findings with the clinical baseline diagnosis or the 2012 ACR/EULAR clinical classification criteria for PMR., Methods: An investigation and a validation cohort were included from two countries, encompassing 66/27 and 36/21 PMR/non-PMR patients, respectively. The cohorts comprised treatment-naïve patients suspected of PMR, who initially received a clinical baseline diagnosis and underwent FDG-PET/CT scans. The FDG-PET/CT Leuven-score was applied to classify patients as either PMR or non-PMR and combined with the clinical baseline diagnosis. Final diagnoses were established through clinical follow-up after twelve or six months in the investigation and validation cohorts, respectively., Results: In the investigation cohort, a clinical baseline diagnosis yielded a sensitivity/specificity of 94%/82%, compared with 78%/70% using the ACR/EULAR criteria. Combining the clinical baseline diagnosis with a positive Leuven-score showed a sensitivity/specificity of 80%/93%, compared with 80%/82% for an ACR/EULAR-Leuven-score. In the validation cohort, the baseline diagnosis revealed a sensitivity/specificity of 100%/91%, compared with 92%/76% using the ACR/EULAR criteria. Combining FDG-PET/CT with the baseline diagnosis demonstrated a sensitivity/specificity of 83%/95% compared with 89%/81% for the ACR/EULAR-Leuven-score., Conclusion: Combining FDG-PET/CT findings with the clinical baseline diagnosis or ACR/EULAR clinical classification criteria can improve the diagnostic specificity for PMR., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: 2-[18F]Fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) has been suggested as an imaging modality to diagnose polymyalgia rheumatica (PMR). However, the applicability of FDG-PET/CT remains unclear, especially following glucocorticoid administration. This study aimed to investigate the diagnostic accuracy of FDG-PET/CT before and during prednisolone treatment, as well as following short-term prednisolone discontinuation., Methods: Treatment naïve suspected PMR patients were clinically diagnosed at baseline and subsequently had an FDG-PET/CT performed. Patients diagnosed with PMR were administered prednisolone following the first FDG-PET/CT and had a second FDG-PET/CT performed after 8 weeks of treatment. Subsequently, prednisolone was tapered with short-term discontinuation at week 9 followed by a third FDG-PET/CT at week 10. An FDG-PET/CT classification of PMR/non-PMR was applied, utilizing both the validated Leuven score and a dichotomous PMR score. The final diagnosis was based on clinical follow-up after 1 year., Results: A total of 68 and 27 patients received a final clinical diagnosis of PMR or non-PMR. A baseline FDG-PET/CT classified the patients as having PMR with a sensitivity/specificity of 86%/63% (Leuven score) and 82%/70% (dichotomous score). Comparing the subgroup of non-PMR with inflammatory diseases to the PMR group demonstrated a specificity of 39%/54% (Leuven/dichotomous score). After 8 weeks of prednisolone treatment, the sensitivity of FDG-PET/CT decreased to 36%/41% (Leuven/dichotomous score), while a short-term prednisolone discontinuation increased the sensitivity to 66%/60%., Conclusion: FDG-PET/CT has limited diagnostic accuracy for differentiating PMR from other inflammatory diseases. If FDG-PET/CT is intended for diagnostic purposes, prednisolone should be discontinued to enhance diagnostic accuracy., Trial Registration: ClinicalTrials.gov (NCT04519580). Registered 17th of August 2020., (© 2024. The Author(s).)

Introduction: Following the approval of tocilizumab (TCZ) for giant cell arteritis (GCA), recent studies have shown a high relapse frequency after abrupt discontinuation of TCZ. However, a thorough exploration of TCZ tapering compared to abrupt discontinuation has never been undertaken. Likewise, adverse events have only been scarcely investigated in routine care. This study aimed to compare the incidence of relapses in GCA patients undergoing TCZ tapering compared to abrupt discontinuation., Methods: We performed a single-center retrospective cohort study from 2012 to 2022. Data from GCA patients treated with TCZ was obtained from the Electronic Patients Record. Relapse-free survival is reported in Kaplan-Meier plots and tapering versus abrupt discontinuation were compared using a Wilcoxon-Brewlos-Gehan test., Results: We included 155 patients receiving TCZ treatment for GCA, of which 104 discontinued TCZ. Among the 104 patients discontinuing TCZ, 42 (40 %) experienced a relapse within the first year. A total of 57 patients underwent taper with 6/38 (16 %) and 2/19 (11 %) relapsing while receiving TCZ every second or third week, respectively. In comparison, 59 patients underwent abrupt discontinuation with 27 (46 %) relapsing during follow-up. The patients undergoing abrupt TCZ discontinuation demonstrated a significantly shorter time to relapse compared to all tapered patients (p = 0.02) as well as patients tapered from weekly TCZ treatment to every second week (p < 0.01). Furthermore, 15 % of patients discontinued TCZ due to adverse events., Conclusion: This is the first study indicating that TCZ taper induced longer relapse-free survival than abrupt discontinuation, implying that taper may be favored over discontinuation in patients with GCA., Competing Interests: Declaration of competing interest BDN has received speaking fees unrelated to this manuscript from Novartis an AbbVie. EMH has received fees unrelated to this manuscript for speaking and/or consulting from Novo, Novartis, AbbVie, Sanofi, Sobi; research funding to Aarhus University Hospital from Independent Research Fund Denmark, Novo Nordic Foundation, Danish Rheumatism Association, Aarhus University, Danish Regions Medicine Grants, Galapagos, AbbVie; travel expenses from Pfizer, Sobi, AbbVie. EMH has been the principal investigator in trials by SynACT Pharma and involved as site principal investigator in trials by AbbVie, Novartis, Novo Nordisk, Sanofi. All other authors have nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Patients with giant cell arteritis (GCA) primarily have their infections managed by primary care providers and hospitalisation is rarely necessary. Existing studies in GCA focus on infection-related hospitalisations only, whereas the use of antibiotic prescriptions is largely unknown. This study aims to examine the one-year overall infection risk among patients with GCA., Methods: This nationwide observational cohort study included patients aged ≥50 years with a first-time GCA diagnosis in the Danish National Patient Registry (1996-2022). Patients with GCA were matched 1:10 by sex and date of birth with general population individuals and followed from date of diagnosis. Overall infections were defined as redeemed antibiotic prescriptions or infection-related hospitalisations. Utilising a pseudo-observation approach, we assessed 1-year cumulative incidence proportions (CIP), risk differences (RD), and relative risks (RR) of infections., Results: The study included 17 773 incident patients with GCA and 177 730 reference individuals. Patients with GCA had a 1-year CIP of 52.4% (95% CI: 51.7-53.2) for overall infections and 17.6% (95% CI: 17.1-18.2) for infection-related hospitalisations. Compared with the reference cohort, patients with GCA had a RR of 1.40 (95% CI: 1.38-1.42) for overall infections and 2.71 (95% CI: 2.61-2.82) for infection-related hospitalisations. Additionally, higher cumulative glucocorticoid doses, advanced age (≥70 years), and higher comorbidity were associated with an increased risk of infections among patients with GCA., Conclusions: The use of antibiotic prescriptions and infection-related hospitalisations in the first year after a GCA diagnosis is high compared with the background population. The cumulative glucocorticoid dose is associated with the infection risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Neurosarcoidosis is a rare and serious condition. Rapid diagnosis and treatment are crucial to prevent morbidity and mortality. When neurological symptoms are not present at the time of diagnosis, CNS involvement can be undetected. We present a case of neurosarcoidosis complicating Löfgren's syndrome and discus the challenges in diagnostics and treatment, that can be encountered.

Objectives: We evaluated sensitivity to change and discriminative abilities of vascular US scores in disease monitoring in the follow-up of a prospective cohort of new-onset cranial and large-vessel (LV) GCA patients., Methods: Baseline and follow-up (8 weeks, 24 weeks and 15 months) US of temporal arteries (TA), carotid and axillary arteries (LV) included assessment of halo and measurement of the intima media complex (IMC). Max IMC, max halo IMC, sum IMC, sum halo IMC, mean IMC, halo count and the Southend halo score were calculated. The provisional OMERACT US score, OGUS, was obtained, taking the average of temporal arteries and axillary arteries IMCs divided by their normal cut-off values., Results: Baseline US was positive in 44/47 patients (72% TA, 72% LV). Sensitivity to change of all composite US scores containing TAs was evident by week 8 onward. LVs responded poorly and new axillary US lesions emerged in six patients despite clinical remission. The OGUS showed a large magnitude of change and is considered the score least prone to potential bias. All TA-based US scores showed moderate-strong correlation with disease activity markers. OGUS, TA halo count, Southend TA halo score, TA sum IMC and TA mean IMC showed potential to discriminate remission and relapse with area under the curve ≥0.8., Conclusions: The OGUS is suggested as an outcome measurement for the assessment of treatment response in clinical trials. The abilities of US scores to discriminate remission and relapse are encouraging and should be further explored., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To explore current management practices for PMR by general practitioners (GPs) and rheumatologists including implications for clinical trial recruitment., Methods: An English language questionnaire was constructed by a working group of rheumatologists and GPs from six countries. The questionnaire focused on: 1: Respondent characteristics; 2: Referral practices; 3: Treatment with glucocorticoids; 4: Diagnostics; 5: Comorbidities; and 6: Barriers to research. The questionnaire was distributed to rheumatologists and GPs worldwide via members of the International PMR/Giant Cell Arteritis Study Group., Results: In total, 394 GPs and 937 rheumatologists responded to the survey. GPs referred a median of 25% of their suspected PMR patients for diagnosis and 50% of these were returned to their GP for management. In general, 39% of rheumatologists evaluated patients with suspected PMR >2 weeks after referral, and a median of 50% of patients had started prednisolone before rheumatologist evaluation. Direct comparison of initial treatment showed that the percentage prescribing >25 mg prednisolone daily for patients was 30% for GPs and 12% for rheumatologists. Diagnostic imaging was rarely used. More than half (56%) of rheumatologists experienced difficulties recruiting people with PMR to clinical trials., Conclusion: This large international survey indicates that a large proportion of people with PMR are not referred for diagnosis, and that the proportion of treatment-naive patients declined with increasing time from referral to assessment. Strategies are needed to change referral and management of people with PMR, to improve clinical practice and facilitate recruitment to clinical trials., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To develop an Outcome Measures in Rheumatology (OMERACT) ultrasonography score for monitoring disease activity in giant cell arteritis (GCA) and evaluate its metric properties., Methods: The OMERACT Instrument Selection Algorithm was followed. Forty-nine members of the OMERACT ultrasonography large vessel vasculitis working group were invited to seven Delphi rounds. An online reliability exercise was conducted using images of bilateral common temporal arteries, parietal and frontal branches as well as axillary arteries from 16 patients with GCA and 7 controls. Sensitivity to change and convergent construct validity were tested using data from a prospective cohort of patients with new GCA in which ultrasound-based intima-media thickness (IMT) measurements were conducted at weeks 1, 3, 6, 12 and 24., Results: Agreement was obtained (92.7%) for the OMERACT GCA Ultrasonography Score (OGUS), calculated as follows: sum of IMT measured in every segment divided by the rounded cut-off values of IMTs in each segment. The resulting value is then divided by the number of segments available. Thirty-five members conducted the reliability exercise, the interrater intraclass correlation coefficient (ICC) for the OGUS was 0.72-0.84 and the median intrareader ICC was 0.91. The prospective cohort consisted of 52 patients. Sensitivity to change between baseline and each follow-up visit up to week 24 yielded standardised mean differences from -1.19 to -2.16, corresponding to large and very large magnitudes of change, respectively. OGUS correlated moderately with erythrocyte sedimentation rate, C reactive protein and Birmingham Vasculitis Activity Score (corr coeff 0.37-0.48)., Conclusion: We developed a provisional OGUS for potential use in clinical trials., Competing Interests: Competing interests: CDe has received grant support from AbbVie and consulting/speaker’s fees from Abbvie, Eli Lilly, Janssen, Galapagos, Novartis, Pfizer, Sparrow, Roche and Sanofi, all unrelated to this manuscript. CPo is or has been the principal investigator of studies by AbbVie, Sanofi and Novartis and has received consulting/speaker’s fees from Vifor, AstraZeneca, GlaxoSmithKline and Roche, all unrelated to this manuscript. LT received speakers fee from Roche, Novartis, Janssen, Pfizer, UCB and GE. PB received grant support from Pfizer and speaker’s fees from Janssen. CDu has received consultancy or speaker fees and travel expenses from Abbvie, AOP Orphan, Astra-Zeneca, Bristol-Myers-Squibb, Eli-Lilly, Janssen, Galapagos, Merck-Sharp-Dohme, Novartis, Pfizer, Roche, Sandoz, UCB, Vifor and research support from Eli-Lilly, Pfizer, UCB, all unrelated to this manuscript. E-MH has received fees for speaking and/or consulting from Novartis, AbbVie, Sanofi, Sobi; research funding to Aarhus University Hospital from Novo Nordic Foundation, Danish Rheumatism Association, Danish Regions Medicine Grants, Roche, Novartis, AbbVie; travel expenses from Pfizer, Sobi, AbbVie. E-MH has been the principal investigator of studies by SynACT Pharma and involved as site principal investigator in trials by AbbVie, Novartis, Novo and Sanofi, all unrelated to this manuscript. AI received honoraria, advisory boards, speakers’ bureau, educational grants and research support from AbbVie, Alfasigma, Amgen, Biogen, BMS, Celgene, Celltrion, Eli-Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer, Sanofi Genzyme, SOBI and UCB. KDT is or was a research investigator of studies for Novartis, Astra Zeneca, Glaxo SmithKline, Amgen; has received consulting fees from Aurinia, Novartis and Astra Zeneca; and is a contracted researcher of Bioclinica. KSMvdG received a speaker fee from Roche. WAS is or has been the principal investigator of studies by Abbvie, Amgen, GlaxoSmithKline, Novartis, Roche, Sanofi and has received consulting/speaker’s fees from Abbvie, Amgen, Bristol-Myers Squibb, Chugai, GlaxoSmithKline, Johnson & Johnson, Medac, Novartis, Roche and Sanofi, all unrelated to this manuscript. The other authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To investigate the risk of ocular manifestations leading to hospital contacts among patients with giant cell arteritis (GCA)., Methods: A Danish, nationwide, register-based cohort study including 14,574 GCA patients diagnosed 1996-2018 and 145,740 general population referents, matched on sex and date of birth. Cumulative incidence proportions (CIPs) and relative risks (RRs) of ocular manifestations with 95% confidence intervals (CIs) were calculated using a pseudo-observation approach., Results: A total of 1026/14,574 (7.0%) GCA patients were registered with ocular manifestations within ±1 year of the diagnosis; 392/1026 (38%) being before and 634/1026 (62%) after the GCA diagnosis, and 744/1026 (73%) were registered within ±1 month of the diagnosis. The diagnoses were 336/1026 (33%) retinal vascular occlusions, 300/1026 (29%) disorders of the optic nerve, 177/1026 (17%) visual impairment, 90/1026 (9%) diplopia, and 123/1026 (12%) amaurosis fugax. The CIP for ocular manifestations among GCA patients after 3, 6, and 12 months following the diagnosis were 4.0% (95% CI: 3.6-4.3), 4.2% (95% CI: 3.9-4.6), and 4.6% (95% CI: 4.2-4.9). The 1-year RR of ocular manifestations among GCA patients was 28.0 (95% CI: 24.0-32.7), with age above 70 years, male sex, and a positive temporal artery biopsy being risk factors. Treatment with low-dose aspirin was not associated with a reduced 1-year RR of incident ocular manifestations., Conclusions: In GCA, most cases of ocular manifestations leading to hospital contacts occur close to the time of diagnosis, with over one-third of cases occurring before the diagnosis, emphasizing the need for early recognition and treatment., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the risk of aortic aneurysms (AA), aortic dissections (AD) and peripheral arterial disease (PAD) among patients with GCA., Methods: In this nationwide, population-based cohort study using Danish national health registries, we identified all incident GCA patients ≥50 years between 1996 and 2018 who redeemed three or more prescriptions for prednisolone. Index date was the date of redeeming the third prednisolone prescription. Case definition robustness was checked through sensitivity analysis. We included general population referents matched 1:10 by age, sex and calendar time. Using a pseudo-observation approach, we calculated 5-, 10- and 15-year cumulative incidence proportions (CIP) and relative risks (RR) of AA, AD and PAD with death as a competing risk., Results: We included 9908 GCA patients and 98 204 referents. The 15-year CIP of thoracic AA, abdominal AA, AD and PAD in the GCA cohort were 1.9% (95% CI 1.5, 2.2), 1.8% (1.4-2.2), 1.0% (0.7-1.2) and 4.8% (4.2-5.3). Compared with the referents, the 15-year RR were 11.2 (7.41-16.9) for thoracic AA, 6.86 (4.13-11.4) for AD, 1.04 (0.83-1.32) for abdominal AA and 1.53 (1.35-1.74) for PAD. Among GCA patients, female sex, age below 70 years and positive temporal artery findings were risk factors for developing thoracic AA. The median time to thoracic AA was 7.5 years (interquartile range 4.4-11.2) with a number needed to be screened of 250 (167-333), 91 (71-111) and 53 (45-67) after 5, 10 and 15 years., Conclusion: Patients with GCA have a markedly increased risk of developing thoracic AA and AD, but no increased risk of abdominal AA., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To investigate whether GCA is associated with increased all-cause and cause-specific mortality., Methods: A nationwide, population-based cohort study in Denmark using medical and administrative registries. GCA cases were defined as patients aged ≥50 years from 1996-2018 with a first-time discharge diagnosis of GCA and ≥3 prescriptions for prednisolone within 6 months following diagnosis. Each GCA patient was matched based on age, sex and calendar time to 10 persons without a history of GCA. Index date was the date for the third prednisolone prescription. We used a pseudo-observation approach to calculate all-cause and cause-specific mortality, adjusted risk differences (RDs) and relative risks (RRs)., Results: We included 9908 GCA patients and 98 204 persons from the general population. The median time for GCA patients to redeem the third prednisolone prescription was 74 days [interquartile range (IQR: 49-106)]. Among GCA patients, the overall mortality was 6.4% (95% CI: 5.9, 6.9) 1 year after index date and 45% (95% CI: 44, 47) after 10 years. Compared with the reference cohort, adjusted RDs and RRs of deaths in the GCA cohort were 2.2% (95% CI: 1.7, 2.7) and 1.49 (95% CI: 1.36, 1.64) after 1 year, and 2.1% (95% CI: 1.0, 3.3) and 1.03 (95% CI: 1.00, 1.05) 10 years after index date. GCA patients had a higher risk of death due to infectious, endocrine, cardiovascular and gastrointestinal diseases., Conclusions: GCA is associated with increased all-cause mortality, particularly within the first year following the diagnosis. Cause-specific mortality indicates that mortality in GCA may in part be due to glucocorticoid-related complications., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To define chronic ultrasound lesions of the axillary artery (AA) in long-standing giant cell arteritis (GCA) and to evaluate the reliability of the new ultrasound definition in a web-based exercise., Methods: A structured Delphi, involving an expert panel of the Large Vessel Vasculitis subgroup of the Outcome Measures in Rheumatology (OMERACT) Ultrasound Working Group was carried out. The reliability of the new definition was tested in a 2-round web-based exercise involving 23 experts and using 50 still images each from AA of long-standing and acute GCA patients, as well as 50 images from healthy individuals., Results: The final OMERACT ultrasound definition of chronic changes was based on measurement and appearance of the intima-media complex. The overall reliability of the new definition for chronic ultrasound changes in longstanding GCA of the AA was good to excellent with Light's kappa values of 0.79-0.80 for inter-reader reliability and mean Light's-kappa of 0.88 for intra-reader reliability. The mean inter-rater and intra-rater agreements were 86-87% and 92%, respectively. Good reliabilities were observed comparing the vessels with longstanding versus acute GCA with a mean agreement and kappa values of 81% and 0.63, respectively., Conclusion: The new OMERACT ultrasound definition for chronic vasculitis of the AA in GCA revealed a good to excellent inter- and intra-reader reliability in a web-based exercise of experts., Competing Interests: Declaration of Competing Interest None of the authors declare any competing interest with the present study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: The study investigated the development over time of the incidence, diagnostic imaging, and treatment of giant cell arteritis (GCA)., Method: This nationwide, population-based cohort study was conducted in Denmark using medical and administrative registries. Incident GCA cases from 1996-2018 were defined as patients aged ≥50 years registered with a first-time GCA diagnosis and ≥3 prescriptions for glucocorticoids (GCs) within 6 months after diagnosis. We determined incidence rates of GCA, the proportion of patients still receiving GCs >2 years after diagnosis, the proportion of patients receiving temporal artery biopsies (TAB) and diagnostic imaging including ultrasound, positron emission tomography, magnetic resonance, and/or computed tomography angiography at the time of diagnosis., Results: We identified 9908 incident GCA cases. The incidence rates of GCA remained stable at 19-25 per 100,000 people aged >50 years from 1996-2018. The proportion of GCA patients receiving a TAB remained constant until 2016, after which it promptly declined from 70-80% to 29-39%. In contrast, the proportion of patients receiving diagnostic imaging increased from 2% to 66% from 2000-2018. The proportion of GCA patients remaining in GC treatment has steadily decreased from 1996-2016, but remains high at 64%, 40%, and 34% after 2, 5, and 10 years following the diagnosis, respectively. The cumulative GC dose has remained relatively stable., Conclusion: Incidence rates of GCA have remained stable since 1996 despite increasing use of diagnostic imaging. There is a clear discrepancy between current international GCA treatment guidelines and the clinical practice up to 2018., Competing Interests: Declaration of Competing Interest Authors declare no conflicts of interest and the views expressed are those of the authors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: The diagnostic accuracy of axillary artery US in the diagnosis of large-vessel (LV)-GCA using 18F-fluorodeoxyglucose (FDG) PET/CT as reference standard was prospectively evaluated in GCA-suspected patients. As an exploratory analysis, the diagnostic accuracy of cranial artery FDG PET/CT was evaluated., Methods: Briefly, the inclusion criteria were age ≥50 years, raised inflammatory markers and potential GCA symptoms. Patients in immunosuppressive therapy or with a previous diagnosis of GCA or PMR were excluded. Examinations were performed pre-treatment. LV-GCA reference diagnosis was a clinical diagnosis of GCA and PET-proven LV inflammation. GCA patients fulfilling ACR criteria were considered as cranial-GCA (c-GCA). Patients without GCA were considered controls. Receiver operating characteristic curve analysis of the US-measured axillary intima-media thickness was performed. FDG uptake in temporal, maxillary and vertebral arteries was also assessed., Results: Forty-six patients were diagnosed with LV-GCA, 10 with isolated c-GCA, and in 34 patients GCA was dismissed. Axillary US yielded a sensitivity of 76% and a specificity of 100% for LV-GCA. An axillary intima-media thickness cut-off of 1.0 mm yielded a sensitivity of 74% and a specificity of 92%. Adding LV US to temporal assessment increased sensitivity from 71% to 97% (all GCA patients). Cranial artery PET showed a diagnostic sensitivity of 78% and specificity of 100% for c-GCA., Conclusion: Axillary artery US shows high accuracy for the LV-GCA diagnosis. Building upon the recent EULAR recommendations, we propose a diagnostic algorithm with US as the first-line confirmatory test, not only in c-GCA-suspected patients, but in all patients suspected of GCA., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study aimed to characterize the association between HLA alleles and ANCA-associated vasculitis (AAV) in a genetically homogeneous population, and to analyse the contribution of specific HLA molecule amino acid sequences to the risk of AAV., Methods: We included 187 Danish patients with AAV and 1070 healthy controls. All were HLA typed at two-field resolution. The association of HLA alleles to PR3- or MPO-AAV was analysed. The contribution of the dominant molecular motifs of the HLA-DPB1 molecule to the risk of AAV was investigated by association studies that included specific amino acid sequences of the hypervariable regions in exon 2., Results: Ninety-four percent of patients with PR3-AAV were carriers of HLA-DPB1*04:01 while all patients with PR3-AAV were carriers of an HLA-DPB1*04 allele, and 85% were homozygous. This was significantly more than in the control group (P < 0.0001). The association was even stronger when HLA-DPB1*04:02 and -DPB1*23:01 were included. HLA-DPB1*04:01, -DPB1*04:02 and -DPB1*23:01 share amino acids in positions 8-9, 69, 76 and 84-87 within the hypervariable regions, but only positions 69 and 84-87 contributed significantly to the disease risk. HLA-DRB1*15 was associated with an increased risk of developing PR3-AAV, while HLA-DRB1*04, -DRB1*07 and -DQB1*03 were associated with a reduced risk of kidney involvement in PR3-AAV. MPO-AAV was only weakly associated with HLA class I alleles., Conclusion: PR3-AAV is strongly associated with the HLA-DPB1 alleles HLA-DPB1*04:01, -DPB1*04:02 and -DPB1*23:01, which share amino acid sequences crucial for the peptide-binding groove., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To investigate the in-situ expression of acetylcholinesterase (AChE) in the inflamed vessel wall of patients with biopsy-positive giant cell arteritis (GCA) as compared to biopsy-negative non-GCA patients, and to evaluate the in-vivo expression of AChE in patients with large-vessel GCA (LVGCA) by 11C-donepezil (AChE inhibitor) positron emission tomography/computed tomography (PET/CT)., Methods: Twenty-four biopsy-positive GCA and 44 biopsy-negative non-GCA patients were included for AChE histology. Immunohistochemical methods were used to determine the AChE expression. The histological inflammation and the AChE expression were assessed by an experienced pathologist on a 3-point scale. Two patients with newly diagnosed 18F-fluorodeoxyglucose (18F-FDG) PET/CT verified LVGCA were included for 11C-donepezil PET/CT. PET images were assessed by an experienced nuclear medicine physician., Results: AChE was expressed in all 24 positive temporal artery biopsies, 10/24 showed high AChE expression (grade 2) and 14/24 showed moderate AChE expression (grade 1). No AChE expression was observed outside the media smooth muscle cells (grade 0) in any of the biopsy-negative non-GCA patients. The AChE expression was in 86% agreement with the histological inflammation. The AChE expression was not associated with any clinical or biochemical findings. In both LV-GCA patients, PET/CT revealed extensive vascular FDG uptake but no 11C-donepezil uptake., Conclusions: AChE is highly expressed in the inflamed vessel wall of patients with GCA. Although, 11C-donepezil PET/CT showed no vascular uptake in the FDG PET/CT verified LV-GCA patients, histological findings raise the possibility that AChE can be used in the development of new diagnostic and disease monitoring tools for GCA.

Purpose: To estimate the diagnostic accuracy of conventional 18F-FDG PET/CT of cranial arteries in the diagnosis of giant cell arteritis (GCA)., Methods: The study was a retrospective case-control study. The reference diagnosis was fulfillment of the 1990 ACR criteria for GCA. All patients had new-onset GCA. Conventional 18F-FDG PET/CT was performed before glucocorticoid treatment. Controls were age- and sex-matched patients with a previous history of malignant melanoma (MM) undergoing surveillance PET/CT >6 months after MM resection. PET images were evenly cropped to include only head and neck and were assessed in random order by four nuclear medicine physicians blinded to reference diagnosis. Temporal (TA), maxillary (MA) and vertebral (VA) arteries were visually rated for 18F-FDG uptake. Interreader agreement was evaluated by Fleiss kappa., Results: A total of 44 patients and 44 controls were identified. In both groups, the mean age was 69 years (p = 0.45) and 25/44 were women. 35/41 GCA patients were temporal artery biopsy positive (TAB). Considering only FDG uptake in TA and/or MA, diagnostic sensitivity and specificity was 64 and 100%. Including VA, sensitivity increased to 82% and specificity remained 100%. Interreader agreement was 91% and Fleiss kappa 0.82 for the PET diagnosis based on the cranial arteries., Conclusion: Conventional 18F-FDG PET/CT is an accurate and reliable tool to diagnose cranial arteritis in glucocorticoid-naïve GCA patients. The high diagnostic specificity suggests that TAB can be omitted in patients with 18F-FDG uptake in cranial arteries. 18F-FDG PET/CT performed in patients with suspected vasculitis should always include the head and neck.

Purpose: To evaluate the in-treatment diagnostic accuracy of FDG PET/CT in large-vessel giant cell arteritis (LV-GCA) by serial scans before and after a short course of high-dose glucocorticoid treatment., Methods: Twenty-four glucocorticoid-naïve patients with new-onset PET/CT verified LV-GCA (pre-treatment baseline PET) were prospectively included. Excluded were patients with a previous history of GCA or polymyalgia rheumatica, LV-GCA-mimicking conditions and patients on immunosuppressive therapy. All patients were treated with 60 mg of oral prednisolone daily and assigned for in-treatment FDG PET/CT after either 3 (PET3) or 10 days (PET10). Two experienced nuclear medicine physicians, blinded to patients' clinical data, reviewed the FDG PET/CT images. A visual semi-quantitative approach was used. Segmental and homogenous FDG uptake in the wall of the aorta and/or supra-aortic branches with higher uptake intensity than liver was considered consistent with vasculitis. Inter-reader reliability was evaluated., Results: Although glucocorticoid treatment attenuated FDG uptake in large vessels, LV-GCA was accurately diagnosed in 10/10 patients after 3 days of treatment, but only in 5/14 patients after 10 days of treatment (p < 0.001). Interrater reliability was substantial (agreement 87%, Cohen's weighted kappa 0.70). No correlation between CRP and FDG uptake was found., Conclusions: Within 3 days of high-dose glucocorticoid treatment, FDG PET/CT can diagnose LV-GCA with high sensitivity. This window of opportunity ensures that prompt glucocorticoid treatment can be initiated to avoid debilitating GCA complications with a limited effect on diagnostic accuracy. After 10 days of treatment, FDG PET/CT sensitivity decreases significantly.

The aim of this study was to determine the effects of persistent organic pollutants (POPs) and biometric variables on circulating levels of steroid hormones (androgens, estrogens and progestagens) in male polar bears (Ursus maritimus) from Svalbard, Norway (n = 23). Levels of pregnenolone (PRE), progesterone (PRO), androstenedione (AN), dehydroepiandrosterone (DHEA), testosterone (TS), dihydrotestosterone (DHT), estrone (E1), 17α-estradiol (αE2) and 17β-estradiol (βE2) were quantified in polar bear serum by gas chromatography tandem mass spectrometry (GC-MS/MS), while POPs were measured in plasma. Subsequently, associations between hormone concentrations (9 steroids), POPs (21 polychlorinated biphenyls (PCBs), 8 OH-PCBs, 8 organochlorine pesticides (OCPs) and OCP metabolites, and 2 polybrominated diphenyl ethers (PBDEs)) and biological variables (age, head length, body mass, girth, body condition index), capture date, location (latitude and longitude), lipid content and cholesterol levels were examined using principal component analysis (PCA) and orthogonal projections to latent structures (OPLS) modelling. Average concentrations of androgens, estrogens and progestagens were in the range of 0.57-83.7 (0.57-12.4 for subadults, 1.02-83.7 for adults), 0.09-2.69 and 0.57-2.44 nmol/L, respectively. The steroid profiles suggest that sex steroids were mainly synthesized through the Δ-4 pathway in male polar bears. The ratio between androgens and estrogens significantly depended on sexual maturity with androgen/estrogen ratios being approximately 60 times higher in adult males than in subadult males. PCA plots and OPLS models indicated that TS was positively related to biometrics, such as body condition index in male polar bears. A negative relationship was also observed between POPs and DHT. Consequently, POPs and body condition may potentially affect the endocrinological function of steroids, including development of reproductive tissues and sex organs and the general condition of male polar bears., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The term anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) covers a group of rare diseases with inflammation in the small vessels and associated with the presence of ANCA. The patients can present with signs and symptoms from almost all organs. In primary care as well as in hospitals AAV is important to acknowledge as differential diagnosis to cancer and infectious diseases, because low morbidity and mortality related to AAV is dependent on early diagnosis and timely treatment. Patients suspected of AAV should be finally diagnosed and treated at specialized centres.

Objective: The long-term cancer risk for patients treated for granulomatosis with polyangiitis (GPA) is not well characterized. We assessed the risk of early and late-occurring cancers among 293 patients diagnosed with GPA from 1973 to 1999 and followed throughout 2010., Methods: Cancer incidence in the cohort was determined by linkage with the Danish Cancer Registry and compared with that in the general population by calculation of standardized incidence ratios (SIRs)., Results: The median duration of follow-up was 9.7 years (range 0-36). Seventy-three cancers occurred, of which 30 were non-melanoma skin cancers (NMSCs) and 11 were bladder carcinomas. A high occurrence of NMSC was observed from the second year of follow-up onwards, with a SIR of 7.0 (95% CI 2.3, 16) for cases diagnosed ≥20 years after GPA. The incidence of bladder cancer increased after 5-9, 10-14 and 15-19 years of follow-up, with SIR estimates for these latency periods of 5.3 (95% CI 1.1, 15), 14.4 (95% CI 5.3, 31) and 10.5 (95% CI 1.2, 38), respectively. The incidence of myeloid leukaemia was significantly increased during years 5-9 [SIR 23.9 (95% CI 2.7, 86)]. Increased incidence of NMSC, bladder cancer and myeloid leukaemia was observed among patients exposed to cumulative CYC doses >36 g, while the only malignancy type observed in excess among those treated with lower CYC doses was NMSC. The cancer risk among CYC-naive patients was not significantly increased., Conclusion: GPA patients experience a greater than expected number of specific malignancies following conventional therapies. Our analyses demonstrate a substantially increased risk of very late-occurring NMSC and bladder cancer in this patient group., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Rheumatoid arthritis (RA) is a systemic chronic inflammatory joint disease, whereas osteoarthritis (OA) is a local joint disease with low-level inflammatory activity. The pathogenic role of the adipocytokine adiponectin is largely unknown in these diseases. We hypothesized (1) that plasma adiponectin concentrations differ in healthy controls and patients with early disease-modifying antirheumatic drug (DMARD)-naive RA, chronic RA, and OA; (2) that changes in adiponectin are observed during methotrexate (MTX) treatment of chronic RA; and (3) that adiponectin correlates to disease activity measures in RA., Methods: Plasma adiponectin was analyzed with a validated in-house immunoassay. We measured adiponectin in healthy controls (n = 45) and patients with early DMARD-naive RA (n = 40), chronic RA (n = 74), and OA (n = 35). In a subgroup of patients with chronic RA (n = 31), the longitudinal effect of MTX treatment on adiponectin (Week 0 vs Week 28) was investigated., Results: Adiponectin differed significantly between healthy controls (mean 4.8 +/- SD 2.7 mg/l) and the 3 groups, with 8.9 +/- 4.8 mg/l in early RA, 11.6 +/- 5.6 mg/l in chronic RA, and 14.1 +/- 6.4 mg/l in OA. Longitudinally, MTX treatment increased adiponectin significantly from 9.7 +/- 4.5 mg/l at Week 0 to 11.0 +/- 4.5 mg/l at Week 28 in chronic RA. No correlations to disease activity measures were found., Conclusion: Both early DMARD-naive and chronic RA were associated with higher plasma adiponectin compared to healthy controls, but lower plasma adiponectin than OA. Adiponectin increased 13% during MTX treatment. In patients with RA and OA body mass index, age, sex, and disease activity measures failed to explain the findings.