Impact of TNF inhibitor medication on working ability in axial spondyloarthritis: an observational national registry-based cohort study.

Objective: The aim was to investigate the effect of TNF inhibitor (TNFi) initiation on working ability and health-care resource utilization among axial SpA patients in a real-life setting. Methods: Patients with a clinical diagnosis of non-radiographic (nr-axSpA) or radiographic axial SpA initiating their first TNFi were identified from the National Register for Antirheumatic and Biologic Treatment in Finland. Sickness absences, including sick leave and disability pension, in- and outpatient days and rehabilitation rates, 1 year before and after initiating the medication were retrieved from national registries. Factors affecting result variables were studied using multivariate regression analysis. Results: Overall, 787 patients were identified. Rates of work disability days per year were 55.6 the year before treatment onset and 55.2 the year after, with significant differences between patient subgroups. The rate of sick leave decreased after starting TNFi treatment. However, the rate of disability pension continued to rise. Patients with a diagnosis of nr-axSpA experienced a decrease in overall work disability and, especially, fewer sick leaves. No sex differences were detected. Conclusion: TNFi interrupts the increase in work disabled days evident during the year before its initiation. However, the overall work disability remains high. Treating patients earlier in the nr-axSpA phase, regardless of sex, appears important in maintaining the ability to work.

The Delay and Costs of Diagnosing Systemic Vasculitis in a Tertiary-Level Clinic.

INTRODUCTION: The diagnosis of systemic vasculitis is a challenge because of the heterogeneity of clinical manifestations. The aim of this study is to analyze the diagnostic delay in systemic vasculitis, the total costs during the first year of care, and how the diagnostic delay affects the costs in a tertiary health care facility. METHODS: Patients with a new diagnosis of systemic vasculitis between 2010 and 2018 were identified from hospital records. The diagnostic delay and health care costs were evaluated during the diagnostic period and within 12 months after the first contact with tertiary health care. Vasculitis-related costs were recorded as true costs charged. A total of 317 patients fulfilled the study criteria. The diagnoses were grouped into three clinically relevant groups: IgA vasculitis and other small-vessel vasculitis (n = 64), ANCA-associated vasculitis (AAV) (n = 112), and large-vessel vasculitis (LVV) (n = 141). RESULTS: The diagnostic delay from the first referral to tertiary-level clinic was shortest in the LVV group and longest in the AAV group. Total costs during the diagnostic period were the highest in the AAV group (median = €6754 [IQR €8812]) and lowest in the LVV group (median = €3123 [IQR €4517]), p < 0.001. There was a significant positive correlation between the diagnostic delay and total costs during the diagnostic period and 12 months (rs = 0.38, p < 0.001 and rs = 0.34, p < 0.001, respectively). In a linear model, the inpatient days and the number of laboratory tests were the strongest predictors (p < 0.001) of a higher treatment cost during the diagnostic period. CONCLUSIONS: There is a substantial diagnostic delay that correlates significantly with the costs in tertiary-level health care when diagnosing systemic vasculitis.

First-in-Humans Study of 68Ga-DOTA-Siglec-9, a PET Ligand Targeting Vascular Adhesion Protein 1.

Sialic acid-binding immunoglubulinlike lectin 9 (Siglec-9) is a ligand of vascular adhesion protein 1. A 68Ga-labeled peptide of Siglec-9, 68Ga-DOTA-Siglec-9, holds promise as a novel PET tracer for imaging of inflammation. This first-in-humans study investigated the safety, tolerability, biodistribution, and radiation dosimetry of this radiopharmaceutical. Methods: Six healthy men underwent dynamic whole-body PET/CT. Serial venous blood samples were drawn from 1 to 240 min after intravenous injection of 162 ± 4 MBq of 68Ga-DOTA-Siglec-9. In addition to γ-counting, the plasma samples were analyzed by high-performance liquid chromatography to detect intact tracer and radioactive metabolites. Radiation doses were calculated using the OLINDA/EXM software, version 2.2. In addition, a patient with early rheumatoid arthritis was studied with both 68Ga-DOTA-Siglec-9 and 18F-FDG PET/CT to determine the ability of the new tracer to detect arthritis. Results:68Ga-DOTA-Siglec-9 was well tolerated by all subjects. 68Ga-DOTA-Siglec-9 was rapidly cleared from the blood circulation, and several radioactive metabolites were detected. The organs with the highest absorbed doses were the urinary bladder wall (0.38 mSv/MBq) and kidneys (0.054 mSv/MBq). The mean effective dose was 0.022 mSv/MBq (range, 0.020-0.024 mSv/MBq). Most importantly, however, 68Ga-DOTA-Siglec-9 was comparable to 18F-FDG in detecting arthritis. Conclusion: Intravenous injection of 68Ga-DOTA-Siglec-9 was safe and biodistribution was favorable for testing of the tracer in larger group of patients with rheumatoid arthritis, as is planned for the next phase of clinical trials. The effective radiation dose of 68Ga-DOTA-Siglec-9 was within the same range as the effective radiation doses of other 68Ga-labeled tracers. Injection of 150 MBq of 68Ga-DOTA-Siglec-9 would expose a subject to 3.3 mSv. These findings support the possible repeated clinical use of 68Ga-DOTA-Siglec-9, such as in trials to elucidate the treatment efficacy of novel drug candidates.

Granulocyte colony-stimulating factor- and chemotherapy-induced large-vessel vasculitis: six patient cases and a systematic literature review.

OBJECTIVE: Patients receiving chemotherapy are prone to neutropoenic infections, presenting with non-specific symptoms such as a high fever and elevated inflammatory parameters. Large-vessel vasculitis (LVV) may have a similar clinical presentation and should be included in differential diagnostics. A few published case reports and adverse event reports suggest a causal association between LVV and the use of granulocyte colony-stimulating factor (G-CSF) and chemotherapy. Our objective was to evaluate the relationship between LVV, G-CSF and chemotherapy. METHODS: Between 2016 and 2018, we identified six patients in Finland with probable drug-induced LVV associated with G-CSF and chemotherapy. All six patients had breast cancer. A systematic literature review was performed according to PRISMA guidelines using comprehensive search terms for cancer, chemotherapy, G-CSF and LVV. RESULTS: The literature search identified 18 similar published case reports, of which most were published after 2014. In all patients combined (n = 24), the time delay from the last drug administration to the LVV symptoms was on average 5 days with G-CSF (range = 1-8 days) and 9 days with chemotherapy (range = 1-21 days). Common symptoms were fever (88%), neck pain (50%) and chest pain (42%). Based on imaging, 17/24 (71%) had vascular inflammation in the thoracic aorta and supra-aortic vessels, but 5/24 (21%) reportedly had inflammation limited to the carotid area. CONCLUSION: This review suggests that LVV may be a possible serious adverse event associated with G-CSF and chemotherapy. Successful management of drug-induced LVV requires early identification, through diagnostic imaging, and discontinuation of the drug.

The Clinical Impact of Using 18F-FDG-PET/CT in the Diagnosis of Suspected Vasculitis: The Effect of Dose and Timing of Glucocorticoid Treatment.

18F-Fluorodeoxyglucose positron-emission tomography (18F-FDG-PET) with computed tomography (CT) is effective for diagnosing large vessel vasculitis, but its usefulness in accurately diagnosing suspected, unselected vasculitis remains unknown. We evaluated the feasibility of 18F-FDG-PET/CT in real-life cohort of patients with suspicion of vasculitis. The effect of the dose and the timing of glucocorticoid (GC) medication on imaging findings were in special interest. 82 patients with suspected vasculitis were evaluated by whole-body 18F-FDG-PET/CT. GC treatment as prednisolone equivalent doses at the scanning moment and before imaging was evaluated. 38/82 patients were diagnosed with vasculitis. Twenty-one out of 38 patients had increased 18F-FDG accumulation in blood vessel walls indicating vasculitis in various sized vessels. Vasculitis patients with a positive vasculitis finding in 18F-FDG-PET/CT had a significantly shorter duration of GC use (median = 4.0 vs 7.0 days, P=0.034), and they used lower GC dose during the PET scan (median dose = 15.0 mg/day vs 40.0 mg/day, p=0.004) compared to 18F-FDG-PET/CT-negative patients. Vasculitis patients with a positive 18F-FDG-PET/CT result had significantly higher C-reactive protein (CRP) than patients with a negative 18F-FDG-PET/CT finding (mean value = 154.5 vs 90.4 mg/L, p=0.018). We found that 18F-FDG-PET/CT positivity was significantly associated with a lower dose and shorter duration of GC medication and higher CRP level in vasculitis patients. 18F-FDG-PET/CT revealed clinically significant information in over half of the patients and was effective in confirming the final diagnosis.

Cost-effectiveness of abatacept, tocilizumab and TNF-inhibitors compared with rituximab as second-line biologic drug in rheumatoid arthritis.

OBJECTIVES: The objective of this study was to evaluate the cost-effectiveness of abatacept, tocilizumab, and tumor necrosis factor (TNF) inhibitors as compared with rituximab in Finnish rheumatoid arthritis patients, who have previously been treated with TNF inhibitors. METHODS: A patient-level simulation model was developed to predict costs and outcomes associated with four biological drugs (abatacept, tocilizumab, rituximab and TNF inhibitors) in the treatment of rheumatoid arthritis. Following lack of efficacy or adverse events, the patients were switched to another biological drug until all four options were exhausted. After that, the patients were assumed to receive a 6th line treatment until death. The patients' baseline characteristics and regression models used in the simulation were based on observational data from the National Register for Biological Treatments in Finland. Direct costs comprised drug costs, administration costs, costs of switching, and outpatient and inpatient care, while indirect costs included disability pension and sick leaves due to rheumatoid arthritis. Several subgroup and deterministic sensitivity analyses were conducted. RESULTS: Drug costs were the lowest for rituximab, but when administration costs and costs of switching were included, drug costs were the lowest for TNF inhibitors. Abatacept was associated with the highest drug costs, whereas rituximab was associated with the highest healthcare costs. In total, TNF inhibitors had the lowest direct costs, while rituximab had the highest direct costs. The amount of quality-adjusted life years (QALY) gained ranged from 9.405 for rituximab to 9.661 for TNF inhibitors. TNF inhibitors, abatacept, and tocilizumab were dominant in comparison to RTX. CONCLUSIONS: TNF inhibitors, abatacept, and tocilizumab had lower costs and higher QALYs than rituximab, and therefore, they were dominant in comparison to rituximab. As TNF inhibitors had the lowest costs and highest QALYs, they were the most cost-effective treatment option.

The detection of coronary stiffness in cardiac allografts using MR imaging.

OBJECTIVE: To test the hypothesis that biomechanical changes are quantitatively related to morphological features of coronary arteries in heart transplant (HTx) recipients. MATERIALS AND METHODS: With IRB approval, three-dimensional (3D) magnetic resonance (MR) angiography and two-dimensional (2D) black-blood stead-state free precession (SSFP) MR imaging were performed to image coronary arteries of 36 HTx patients. Contours of coronary wall were manually drawn. For each coronary segment, coronary wall thickness, wall area, lumen area (in systole and diastole) were acquired. Coronary distensibility index (CDI) and the percent of the coronary wall occupying the vessel area (PWOV) were calculated. RESULTS: There are totally 98 coronary segments eligible for quantitative analysis from 27 HTx patients. The CDI is 4.90 ± 2.44 mmHg(-1). The mean wall thickness is 1.49 ± 0.24 mm and the PWOV is 74.6% ± 7.5%. CDI has moderate correlations with wall thickness (r=-0.531, P<0.001) and with PWOV (R=-0.435, P<0.001). CONCLUSIONS: Detected with coronary MR imaging, CDI is quantitatively correlated with the morphological features of the coronary artery in HTx patients. Coronary stiffness has the potential to become an alternative imaging biomarker for the quantitative assessment of the status of cardiac allografts.

Cardiac magnetic resonance T2 mapping in the monitoring and follow-up of acute cardiac transplant rejection: a pilot study.

BACKGROUND: Acute rejection is a major factor impacting survival in the first 12 months after cardiac transplantation. Transplant monitoring requires invasive techniques. Cardiac magnetic resonance (CMR), noninvasive testing, has been used in monitoring heart transplants. Prolonged T2 relaxation has been related to transplant edema and possibly rejection. We hypothesize that prolonged T2 reflects transplant rejection and that quantitative T2 mapping will concur with the pathological and clinical findings of acute rejection. METHODS AND RESULTS: Patients were recruited within the first year after transplantation. Biopsies were graded according to the International Society for Heart Lung Transplant system for cellular rejection with immunohistochemistry for humoral rejection. Rejection was also considered if patients presented with signs and symptoms of hemodynamic compromise without biopsy evidence of rejection who subsequently improved with treatment. Patients underwent a novel single-shot T2-prepared steady-state free precession 4-chamber and 3 short axis sequences and regions of interest were drawn overlying T2 maps by 2 independent blinded reviewers. A total of 74 (68 analyzable) CMRs T2 maps in 53 patients were performed. There were 4 cellular, 2 humoral, and 2 hemodynamic rejection cases. The average T2 relaxation time for grade 0R (n=46) and grade 1R (n=17) was 52.5±2.2 and 53.1±3.3 ms (mean±SD), respectively. The average T2 relaxation for grade 2R (n=3) was 59.6±3.1 ms and 3R (n=1) was 60.3 ms (all P value <0.05 compared with controls). The T2 average in humoral rejection cases (n=2) was 59.2±3.3 ms and the hemodynamic rejection (n=2) was 61.1±1.8 ms (P<0.05 versus controls). The average T2 relaxation time for all-cause rejection versus no rejection is 60.1±2.1 versus 52.8±2.7 ms (P<0.05). All rejection cases were rescanned 2.5 months after treatment and demonstrated T2 normalization with average of 51.4±1.6 ms. No difference was found in ventricular function between nonrejection and rejection patients, except in ventricular mass 107.8±10.3 versus 127.5±10.4 g (P < 0.05). CONCLUSIONS: Quantitative T2 mapping offers a novel noninvasive tool for transplant monitoring, and these initial findings suggest potential use in characterizing rejections. Given the limited numbers, a larger multi-institution study may help elucidate the benefits of T2 mapping as an adjunctive tool in routine monitoring of cardiac transplants.

Black-blood steady-state free precession (SSFP) coronary wall MRI for cardiac allografts: a feasibility study.

PURPOSE: To assess the hypothesis that steady-state free procession (SSFP) allows for imaging of the coronary wall under the conditions of fast heart rate in heart transplantation (HTx) patients. MATERIALS AND METHODS: With the approval of our Institutional Review Board, 28 HTx patients were scanned with a 1.5T scanner. Cross-sectional black-blood images of the proximal portions of the left main artery, left anterior descending artery, and right coronary artery were acquired with both a 2D, double inversion recovery (DIR) prepared turbo (fast) spin echo (TSE) sequence and a 2D DIR SSFP sequence. Image quality (scored 0-3), vessel wall area, thickness, signal-to-noise ratio (SNR, vessel wall), and contrast-to-noise ratio (CNR, wall-lumen) were compared between TSE and SSFP. RESULTS: The overall image quality of SSFP was higher than TSE (1.23 ± 0.95 vs. 0.88 ± 0.69, P < 0.001). SSFP had a higher coronary wall SNR (20.1 ± 8.5 vs. 14.9 ± 4.8, P < 0.001) and wall-lumen CNR (8.2 ± 4.6 vs. 6.8 ± 3.7, P = 0.005) than TSE. CONCLUSION: Black-blood SSFP coronary wall MRI provides higher image quality, SNR, and CNR than traditional TSE does in HTx recipients. It has the potential to become an alternative means to noninvasive imaging of cardiac allografts.

Coronary wall MR imaging in patients with rapid heart rates: a feasibility study of black-blood steady-state free precession (SSFP).

We assessed the hypothesis that black-blood steady-state free precession (SSFP) would provide coronary wall images comparable to images from TSE and have better performance than TSE under conditions of fast heart rate. With IRB approval, thirty participants without a history of coronary artery disease (19 men, 11 women, 26-83 y/o) were scanned with a 1.5 T MR scanner. Cross-sectional black-blood images of the proximal portions of coronary arteries were acquired with a two-dimensional (2D), double inversion recovery (DIR) prepared TSE sequence and a 2D DIR SSFP sequence on the same planes. Image quality (ranked with a 4-point system, scored from 0 to 3), vessel wall area and thickness, signal-to-noise ratio (SNR) of the wall and contrast-to-noise ratio (CNR, wall to lumen) were compared between SSFP and TSE with SPSS software (v 13.0). Totally 28 scans were completed. For SSFP and TSE, there was no difference in image quality. SSFP had a higher SNR (23.7 ± 10.1 vs. 14.4 ± 5.2, P < 0.001) and wall-lumen CNR (8.8 ± 4.5 vs. 6.7 ± 3.2, P = 0.001). Good agreements between measured wall area (r = 0.701, P < 0.001) and thickness (r = 0.560, P < 0.001) were found. For 10 participants with heart rate more than 80 beats/min, the image quality of SSFP was higher than TSE (P = 0.016). SSFP provided image quality and measurement accuracy that was comparable to TSE. With its higher performance under fast heart rate conditions, SSFP may break through the existing thresholds for heart rate and extend clinical applicability of coronary wall MR imaging to a larger population.

Temporal relationship between human parechovirus 1 infection and otitis media in young children.

BACKGROUND: Human parechovirus (HPeV) 1 is a common virus that infects almost everyone during childhood. Because clinical symptoms are poorly documented, we evaluated the symptoms associated with HPeV1 infection in a cohort of children followed prospectively from birth at 3-month intervals. METHODS: Symptoms such as fever, cough, those of the common cold, otitis media, and gastroenteritis were determined from hospital records and from questionnaires administered to the parents of 59 children during regular study visits. HPeV1 infections were diagnosed by measuring neutralizing antibodies in follow-up serum samples. Additionally, HPeV RNA was analyzed in middle ear fluid (MEF) and nasopharyngeal aspirate samples from 33 patients with otitis media by reverse-transcription polymerase chain reaction. RESULTS: Otitis media showed a clear association with HPeV1 infection-it developed in 50% of the 3-month follow-up periods that yielded evidence for HPeV1 infection but in only 14% of the HPeV1-negative periods (odds ratio [OR], 6.14 [95% confidence interval {CI}, 2.75-13.77]). In children with recurring otitis media, MEF samples were positive for HPeV in 15% of episodes. Cough was also associated with HPeV1 infection, but this association was weaker (OR, 3.67 [95% CI, 1.66-8.09]). Other symptoms were not linked to HPeV1 infection. CONCLUSIONS: HPeV1 infections are common in childhood and may cause otitis media and cough.