The Many faces of vasculitis: diagnostic challenges and economic burden

The systemic vasculitides are characterized by inflammation of the blood vessel walls. Most vasculitides are idiopathic but sometimes a triggering event, e.g., medication, can be identified. Vessels of any type and size can be affected, resulting in a wide spectrum of symptoms ranging from mild to multisystemic life-threatening disorders. The rarity of vasculitides and the heterogeneous nature of the diseases present a diagnostic challenge causing diagnostic delay and numerous examinations. Imaging, including positron emission tomography with computed tomography (PET/CT), has an increasing role in the diagnostic work-up. The aim of this study was to evaluate the performance of PET/CT prospectively, in a real-life cohort of patients with suspected vasculitis, to assess the diagnostic delay and total costs of the diagnostic process of systemic vasculitis and to explore the rare association between large vessel vasculitis (LVV), chemotherapy and granulocyte-colony stimulating factor (G-CSF). PET/CT was found effective in diagnosing vasculitis in a cohort of 82 patients. Lower dose and shorter duration of glucocorticoid medication were significantly associated with positive PET/CT vasculitis finding. Overall, PET/CT revealed clinically significant information in 56% of the patients. Among systemic vasculitides, the diagnostic delay was substantial with great individual variability. Diagnostic delay was correlated with higher total costs, but PET/CT was not a significant contributor. LVV and neutropenic infections might present with similar clinical symptoms. We identified six patients with breast cancer who unexpectedly developed acute, non-infectious LVV during chemotherapy. This patient series and a systematic literature review support the previous reports of a rare causal association between LVV, chemotherapy and G-CSF.Vaskuliitin monet kasvot: diagnoosivaiheen haasteet ja taloudellinen taakka Vaskuliitit ovat verisuonen seinämän tulehduksia, jotka immunologisella mekanismilla vaurioittavat suonen seinämää. Vaskuliitin syy on usein tuntematon, mutta joissain harvoissa tapauksissa laukaiseva tekijä, kuten lääkeaine, voidaan tunnistaa. Sairastuneen suonen koko ja sijainti vaikuttavat taudinkuvaan, joka vaihtelee lievistä paikallisoireista vaikeisiin elinvaurioihin. Vaskuliittien harvinaisuus ja oireiden epämääräisyys aiheuttavat diagnoosiviivettä ja laaja-alaisia tutkimuksia. Kuvantamistutkimuksilla, kuten positroniemissiotomografia-tietokonetomografialla (PET/TT), on lisääntyvä merkitys vaskuliittien diagnostiikassa. Tämän tutkimuksen tarkoituksena oli selvittää PET/TT-kuvantamisen merkitystä vaskuliittiepäilyssä, systeemistä vaskuliittia sairastavien potilaiden diagnoosivaiheen viivettä ja kustannuksia sekä tutkia harvinaista yhteyttä suurten suonten vaskuliitin (SSV), kemoterapian ja valkosolukasvutekijähoidon välillä. PET/TT osoittautui hyödylliseksi vaskuliittidiagnostiikassa. Glukokortikoidilääkityksen matalampi annos ja lyhyempi käyttöaika olivat merkitsevästi yhteydessä positiiviseen PET/TT-vaskuliittilöydökseen. PET/TT-kuvantamisessa 56 %:lla potilaista todettiin kliinisesti merkitsevä löydös. Potilailla, joilla oli systeeminen vaskuliitti, diagnoosiviive oli huomattava ja viiveen yksilöllinen vaihtelu suurta. Diagnoosiviiveen ja korkeampien kustannusten välillä oli merkittävä yhteys. Sen sijaan PET/TT ei ollut yksinään merkittävä kustannustekijä. SSV ja neutropeeniset infektiot voivat olla taudinkuvaltaan samankaltaisia. Tunnistimme kuusi rintasyöpää sairastavaa potilasta, joille kehittyi yllättäen akuutti, ei-infektiivinen SSV kemoterapiahoidon aikana. Tämä potilassarja ja aiheesta laadittu systemaattinen kirjallisuuskatsaus puoltavat harvinaista syy-yhteyttä SSV:n, kemoterapian ja valkosolukasvutekijän välillä

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 s = 0.38, p s = 0.34, p p Conclusions There is a substantial diagnostic delay that correlates significantly with the costs in tertiary-level health care when diagnosing systemic vasculitis.</div

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.Peer reviewe

Reumalääkityksen laboratorioseuranta - ohjeet päivitetty

Reumalääkkeiden turvallinen käyttö edellyttää laboratorioseurantaa. Se toteutetaan perusterveydenhuollon ja erikoissairaanhoidon yhteistyönä.Seurantaohjeet on päivitetty yliopistosairaaloiden yhteistyönä. Usean perinteisen reumalääkehoidon laboratorioseurantaa on kevennetty ja uusista lääkkeistä on laadittu ohjeet.Suosituksen sisältö perustuu tutkimustietoon sekä aiempiin kansallisiin ja kansainvälisiin ohjeisiin, asiantuntija-arvioihin ja kliiniseen kokemukseen.</p

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

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.MethodsBetween 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.ResultsThe 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.ConclusionThis 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.</div

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.Peer reviewe

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, ), and they used lower GC dose during the PET scan (median dose = 15.0 mg/day vs 40.0 mg/day, ) 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, ). 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.</p

A Prospective Comparison of F-18-prostate-specific Membrane Antigen-1007 Positron Emission Tomography Computed Tomography, Whole-body 1.5 T Magnetic Resonance Imaging with Diffusion-weighted Imaging, and Single-photon Emission Computed Tomography/Computed Tomography with Traditional Imaging in Primary Distant Metastasis Staging of Prostate Cancer (PROSTAGE)

Background: Computed tomography (CT) and bone scintigraphy (BS) are the imaging modalities currently used for distant metastasis staging of prostate cancer (PCa). Objective: To compare standard staging modalities with newer and potentially more accurate imaging modalities. Design, setting, and participants: This prospective, single-centre trial (NCT03537391) enrolled 80 patients with newly diagnosed high-risk PCa (International Society of Urological Pathology grade group >= 3 and/or prostate-specific antigen [PSA] >= 20 and/or cT >= T3; March 2018-June 2019) to undergo primary metastasis staging with two standard and three advanced imaging modalities. Outcome measurements and statistical analysis: The participants underwent the following five imaging examinations within 2 wk of enrolment and without a prespecified sequence: BS, CT, Tc-99m-hydroxymethylene diphosphonate (Tc-99m-HMDP) single-photon emission computed tomography (SPECT)-CT, 1.5 T whole-body magnetic resonance imaging (WBMRI) using diffusion-weighted imaging, and F-18-prostate-specific membrane antigen-1007 (F-18-PSMA-1007) positron emission tomography(PET)-CT. Each modality was reviewed by two independent experts blinded to the results of the prior studies, who classified lesions as benign, equivocal, or malignant. Pessimistic and optimistic analyses were performed to resolve each equivocal diagnosis. The reference standard diagnosis was defined using all available information accrued during at least 12 mo of clinical follow-up. Patients with equivocal reference standard diagnoses underwent MRI and/or CT to search for the development of anatomical correspondence. PSMA PET-avid lesions without histopathological verification were rated to be malignant only if there was a corresponding anatomical finding suspicious for malignancy at the primary or follow-up imaging. Results and limitations: Seventy-nine men underwent all imaging modalities except for one case of interrupted MRI. The median interval per patient between the first and the last imaging study was 8 d (interquartile range [IQR]: 6-9). The mean age was 70 yr (standard deviation: 7) and median PSA 12 ng/mL (IQR:7-23). The median follow-up was 435 d (IQR: 378-557). Metastatic disease was detected in 20 (25%) patients. The imaging modality F-18-PSMA-1007 PET-CT had superior sensitivity and highest inter-reader agreement. The area under the receiver-operating characteristic curve (AUC) values for bone metastasis detection with PSMA PET-CT were 0.90 (95% confidence interval [CI]: 0.85-0.95) and 0.91 (95% CI: 0.87-0.96) for readers 1 and 2, respectively, while the AUC values for BS, CT, SPECT-CT, and WBMRI were 0.71 (95% CI: 0.58-0.84) and 0.8 (95% CI: 0.67-0.92), 0.53 (95% CI: 0.39-0.67) and 0.66 (95% CI: 0.54-0.77), 0.77 (95% CI: 0.65-0.89) and 0.75 (95% CI: 0.62-0.88), and 0.85 (95% CI: 0.74-0.96) and 0.67 (95% CI: 0.54-0.80), respectively, for the other four pairs of readers. The imaging method F-18-PSMA-1007 PET-CT detected metastatic disease in 11/20 patients in whom standard imaging was negative and influenced clinical decision making in 14/79 (18%) patients. In 12/79 cases, false positive bone disease was reported only by PSMA PET-CT. Limitations included a nonrandomised study setting and few histopathologically validated suspicious lesions. Conclusions: Despite the risk of false positive bone lesions, F-18-PSMA-1007 PET-CT outperformed all other imaging methods studied for the detection of primary distant metastasis in high-risk PCa. Patient summary: In this report, we compared the diagnostic performance of conventional and advanced imaging. It was found that F-18-prostate-specific membrane antigen-1007 positron emission tomography/computed tomography (F-18-PSMA-1007 PET-CT) was superior to the other imaging modalities studied for the detection of distant metastasis at the time of initial diagnosis of high-risk prostate cancer. PSMA PET-CT also appears to detect some nonmetastatic bone lesions. (C) 2020 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology.Peer reviewe

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

Sialic acid-binding immunoglubulin-like lectin 9 (Siglec-9) is a ligand of vascular adhesion protein 1 (VAP-1). A gallium 68-labeled peptide of Siglec-9, 68Ga-DOTA-Siglec-9, holds promise as a novel PET tracer for imaging of inflammation. This first-in-human study investigated the safety, tolerability, biodistribution, and radiation dosimetry of this radiopharmaceutical. Methods: Six healthy males underwent dynamic whole-body PET/CT. Serial venous blood samples were drawn from 1-240 min after intravenous injection of 162 ± 4 MBq of 68Ga-DOTA-Siglec-9. In addition to gamma 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 2.2 software. 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 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 able to detect arthritis comparable to 18F-FDG. Conclusion: Intravenous injection of 68Ga-DOTA-Siglec-9 was safe and biodistribution is favorable for testing of the tracer in larger group of patients with rheumatoid arthritis planned in the next phase of clinical trials. The effective radiation dose of 68Ga-DOTA-Siglec-9 was within the same range as those 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, e.g., in trials aiming to elucidate the treatment efficacy of novel drug candidates